ATF4 (Activating Transcription Factor 4) is a bZIP transcription factor that serves as the central effector of the Integrated Stress Response (ISR). Under basal conditions, ATF4 translation is suppressed by upstream open reading frames (uORFs) in its 5'UTR. Upon cellular stress (ER stress, amino acid deprivation, oxidative stress, mitochondrial stress), phosphorylation of eIF2alpha by stress-sensing kinases (PERK, GCN2, HRI, PKR) leads to preferential translation of ATF4. In the nucleus, ATF4 heterodimerizes with other bZIP transcription factors (CHOP/DDIT3, C/EBP family members, CREB, ATF3) via its leucine zipper domain and binds to cAMP response elements (CRE) and C/EBP-ATF response elements (CARE/AARE) to activate transcription of stress-responsive genes involved in amino acid metabolism (ASNS, SLC7A11), redox homeostasis, autophagy, and apoptosis. ATF4 also plays non-stress roles in osteoblast differentiation and bone development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0000977
RNA polymerase II transcription regulatory region sequence-specific DNA binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF4 is a bZIP transcription factor that binds to CRE and CARE/AARE sequences in promoters to regulate transcription. This molecular function annotation is appropriate and consistent with its well-established role as a sequence-specific DNA-binding transcription factor.
Reason: ATF4's binding to specific regulatory sequences (CRE, CARE/AARE) is extensively documented and represents a core molecular function (PMID:12871976, PMID:11960987).
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
file:human/ATF4/ATF4-deep-research-cyberian.md
model: deep-research
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF4 functions predominantly as a transcriptional activator for stress-responsive genes including ASNS, GRP78/BiP, CHOP, and TRB3. This annotation accurately reflects its primary molecular function.
Reason: ATF4's transcriptional activator function is well-documented. Overexpression of ATF4 increases promoter-driven transcription of target genes (PMID:11960987, PMID:12871976).
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF4 localizes to the nucleus where it functions as a transcription factor. Nuclear localization has been demonstrated by multiple experimental approaches.
Reason: Nuclear localization is essential for ATF4's function as a transcription factor and is well-documented (UniProt, PMID:23123191, PMID:16682973).
Supporting Evidence:
PMID:23123191
Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF4 regulates transcription of numerous genes in response to cellular stress. This biological process annotation captures its core function.
Reason: Regulation of pol II transcription is a central function of ATF4, documented extensively in the ISR and stress response literature.
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
|
|
GO:1990589
ATF4-CREB1 transcription factor complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF4 forms heterodimeric complexes with CREB1 to regulate target gene expression. This complex was identified in the context of GRP78/BiP regulation.
Reason: ATF4-CREB1 complex formation is documented experimentally (PMID:12871976). The IBA annotation is consistent with this evidence.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:1990590
ATF1-ATF4 transcription factor complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF4 forms heterodimeric complexes with ATF1. This was demonstrated in the context of stress-induced transcription.
Reason: ATF4-ATF1 complex formation is documented (PMID:12871976).
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0003677
DNA binding
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ATF4 binds DNA as part of its transcription factor activity. This is a general term appropriate for IEA evidence.
Reason: DNA binding is well-established for ATF4 as a bZIP transcription factor. The more specific term GO:0000977 is also annotated with better evidence.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ATF4 is a well-established transcription factor. This IEA annotation is consistent with experimental evidence.
Reason: Transcription factor activity is a core function of ATF4, confirmed by multiple experimental studies.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Nuclear localization is well-established for ATF4. Duplicate of IBA annotation.
Reason: Consistent with IBA annotation and experimental evidence.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ATF4 is synthesized in the cytoplasm and can shuttle between cytoplasm and nucleus. Under stress, ATF4 accumulates in the nucleus, but cytoplasmic localization is part of its normal biology.
Reason: ATF4 is translated in the cytoplasm and can localize there under basal conditions before stress-induced nuclear accumulation (UniProt).
|
|
GO:0005813
centrosome
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: ATF4 has been reported to localize to the centrosome based on interaction with NEK6 and colocalization studies. This appears to be a non-canonical localization.
Reason: While documented (PMID:20873783), centrosomal localization is not central to ATF4's primary function as a stress-response transcription factor.
|
|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: ATF4 plasma membrane localization may relate to interaction with GABA-B receptors in neurons (by similarity to rat). This is a specialized context.
Reason: Membrane localization via GABBR interaction is a specialized neuronal function, not the core stress-response role.
|
|
GO:0006351
DNA-templated transcription
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: ATF4 participates in DNA-templated transcription as a transcription factor. This is a broad annotation appropriate for IEA.
Reason: Consistent with ATF4's role as a transcription factor.
|
|
GO:0006355
regulation of DNA-templated transcription
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: ATF4 regulates transcription of stress-responsive genes. This is a core function.
Reason: Consistent with ATF4's established role as a transcriptional regulator.
|
|
GO:0016607
nuclear speck
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: ATF4 can be recruited to nuclear speckles following interaction with EP300/p300.
Reason: Nuclear speckle localization is context-dependent and related to EP300 interaction (PMID:16219772), not a primary localization.
|
|
GO:0042981
regulation of apoptotic process
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: ATF4, particularly in partnership with CHOP, can regulate apoptosis during prolonged ER stress. However, this is an outcome of chronic stress signaling rather than ATF4's primary function.
Reason: ATF4's pro-apoptotic role is context-dependent (chronic stress with CHOP) and represents a downstream consequence rather than core function.
|
|
GO:0048511
rhythmic process
|
IEA
GO_REF:0000043 |
KEEP AS NON CORE |
Summary: ATF4 has been implicated in circadian regulation of gene expression through binding to CRE elements in clock gene promoters.
Reason: While ATF4 can regulate circadian genes, this is a secondary function not central to its ISR role.
|
|
GO:0005515
protein binding
|
IPI
PMID:11238952 ATF4 degradation relies on a phosphorylation-dependent inter... |
MODIFY |
Summary: ATF4 interacts with BTRC (beta-TrCP) as part of the SCF ubiquitin ligase complex that targets ATF4 for degradation. This is a functionally relevant interaction.
Reason: Protein binding is too vague. The specific interaction is with BTRC as a substrate of the SCF ubiquitin ligase for proteasomal degradation.
Proposed replacements:
ubiquitin protein ligase binding
Supporting Evidence:
PMID:11238952
ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase.
|
|
GO:0005515
protein binding
|
IPI
PMID:12743605 SKIP3, a novel Drosophila tribbles ortholog, is overexpresse... |
MODIFY |
Summary: Interaction with TRIB3, a pseudokinase that inhibits ATF4 transactivation activity.
Reason: The interaction with TRIB3 represents a specific regulatory mechanism. A more specific term would be preferred.
Proposed replacements:
DNA-binding transcription factor binding
Supporting Evidence:
PMID:12743605
SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia.
|
|
GO:0005515
protein binding
|
IPI
PMID:12812986 DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associa... |
MODIFY |
Summary: Interaction with DISC1 (Disrupted in Schizophrenia 1). DISC1 inhibits ATF4 by disrupting its dimerization and DNA-binding.
Reason: This represents a specific regulatory interaction affecting ATF4 transcription factor activity.
Proposed replacements:
DNA-binding transcription factor binding
Supporting Evidence:
PMID:12812986
DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation.
|
|
GO:0005515
protein binding
|
IPI
PMID:12860379 Functional interaction of the subunit 3 of RNA polymerase II... |
MODIFY |
Summary: Interaction with RPB3 (POLR2C), a subunit of RNA polymerase II. This reflects ATF4's function as a transcription factor.
Reason: This is a functionally relevant interaction with the transcription machinery.
Proposed replacements:
general transcription initiation factor binding
Supporting Evidence:
PMID:12860379
Functional interaction of the subunit 3 of RNA polymerase II (RPB3) with transcription factor-4 (ATF4).
|
|
GO:0005515
protein binding
|
IPI
PMID:16169070 A human protein-protein interaction network: a resource for ... |
MARK AS OVER ANNOTATED |
Summary: High-throughput interaction study. Generic protein binding annotation from large-scale study.
Reason: Generic protein binding from HT study lacks functional specificity.
Supporting Evidence:
PMID:16169070
A human protein-protein interaction network: a resource for annotating the proteome.
|
|
GO:0005515
protein binding
|
IPI
PMID:16189514 Towards a proteome-scale map of the human protein-protein in... |
MARK AS OVER ANNOTATED |
Summary: High-throughput Y2H study. Generic protein binding annotation.
Reason: Generic protein binding from HT study lacks functional context.
Supporting Evidence:
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
|
|
GO:0005515
protein binding
|
IPI
PMID:16343488 Cooperative interaction of Zhangfei and ATF4 in transactivat... |
MODIFY |
Summary: Interaction with CREBZF (Zhangfei). Cooperative transactivation of CRE.
Reason: This is a specific interaction between bZIP transcription factors.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:16343488
2005 Dec 6. Cooperative interaction of Zhangfei and ATF4 in transactivation of the cyclic AMP response element.
|
|
GO:0005515
protein binding
|
IPI
PMID:18330356 Construction and characterization of a normalized yeast two-... |
MARK AS OVER ANNOTATED |
Summary: High-throughput Y2H study. Generic protein binding.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:18330356
Construction and characterization of a normalized yeast two-hybrid library derived from a human protein-coding clone collection.
|
|
GO:0005515
protein binding
|
IPI
PMID:19164757 ERAD inhibitors integrate ER stress with an epigenetic mecha... |
MODIFY |
Summary: Interaction with ATF3 in the context of ER stress response.
Reason: ATF3 is a bZIP transcription factor partner of ATF4.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:19164757
ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells.
|
|
GO:0005515
protein binding
|
IPI
PMID:19447967 Shifted Transversal Design smart-pooling for high coverage i... |
MARK AS OVER ANNOTATED |
Summary: High-throughput interaction mapping study.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:19447967
Shifted Transversal Design smart-pooling for high coverage interactome mapping.
|
|
GO:0005515
protein binding
|
IPI
PMID:20102225 Identification of bZIP interaction partners of viral protein... |
MODIFY |
Summary: Coiled-coil array interaction study with viral and cellular bZIP proteins.
Reason: These are specific bZIP-bZIP interactions.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:20102225
Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
|
|
GO:0005515
protein binding
|
IPI
PMID:20211142 An atlas of combinatorial transcriptional regulation in mous... |
MARK AS OVER ANNOTATED |
Summary: Atlas of transcriptional regulation study.
Reason: Generic protein binding from computational/HT study.
Supporting Evidence:
PMID:20211142
An atlas of combinatorial transcriptional regulation in mouse and man.
|
|
GO:0005515
protein binding
|
IPI
PMID:20936779 A human MAP kinase interactome. |
MODIFY |
Summary: MAP kinase interactome study. Interaction with JUN family.
Reason: Interaction with JUN represents bZIP heterodimerization.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:20936779
A human MAP kinase interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:21408167 New modularity of DAP-kinases: alternative splicing of the D... |
MODIFY |
Summary: Interaction with DAPK2. ATF4 is a substrate of death-associated protein kinases.
Reason: This is a kinase-substrate interaction.
Proposed replacements:
protein kinase binding
Supporting Evidence:
PMID:21408167
New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform.
|
|
GO:0005515
protein binding
|
IPI
PMID:21988832 Toward an understanding of the protein interaction network o... |
MARK AS OVER ANNOTATED |
Summary: Liver interactome study.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:21988832
Toward an understanding of the protein interaction network of the human liver.
|
|
GO:0005515
protein binding
|
IPI
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
MODIFY |
Summary: Systematic bZIP interaction network study. Documents heterodimerization with multiple bZIP partners.
Reason: This study specifically characterizes bZIP-bZIP interactions.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0005515
protein binding
|
IPI
PMID:25241761 Using an in situ proximity ligation assay to systematically ... |
MARK AS OVER ANNOTATED |
Summary: Proximity ligation assay study.
Reason: Generic protein binding annotation.
Supporting Evidence:
PMID:25241761
Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
MARK AS OVER ANNOTATED |
Summary: Large-scale proteome interactome mapping.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network.
|
|
GO:0005515
protein binding
|
IPI
PMID:25910212 Widespread macromolecular interaction perturbations in human... |
MARK AS OVER ANNOTATED |
Summary: Study of genetic variant effects on protein interactions.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:25910212
Widespread macromolecular interaction perturbations in human genetic disorders.
|
|
GO:0005515
protein binding
|
IPI
PMID:26700459 Involvement of Nrf2 in proteasome inhibition-mediated induct... |
MODIFY |
Summary: Interaction with NRF2/NFE2L2 in the context of proteasome inhibition.
Reason: ATF4 and NRF2 cooperate in antioxidant response.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:26700459
Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells.
|
|
GO:0005515
protein binding
|
IPI
PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... |
MARK AS OVER ANNOTATED |
Summary: Alternative splicing effects on protein interactions.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:26871637
Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
|
|
GO:0005515
protein binding
|
IPI
PMID:27107014 An inter-species protein-protein interaction network across ... |
MARK AS OVER ANNOTATED |
Summary: Cross-species protein interaction network.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:27107014
An inter-species protein-protein interaction network across vast evolutionary distance.
|
|
GO:0005515
protein binding
|
IPI
PMID:28514442 Architecture of the human interactome defines protein commun... |
MARK AS OVER ANNOTATED |
Summary: Large-scale interactome study.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
|
|
GO:0005515
protein binding
|
IPI
PMID:29892012 An interactome perturbation framework prioritizes damaging m... |
MARK AS OVER ANNOTATED |
Summary: Interactome perturbation study.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:29892012
Jun 11. An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.
|
|
GO:0005515
protein binding
|
IPI
PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d... |
MODIFY |
Summary: Alzheimer's disease interactome study. Interaction with DISC1.
Reason: DISC1 interaction is functionally relevant for ATF4 regulation.
Proposed replacements:
DNA-binding transcription factor binding
Supporting Evidence:
PMID:31413325
HENA, heterogeneous network-based data set for Alzheimer's disease.
|
|
GO:0005515
protein binding
|
IPI
PMID:31515488 Extensive disruption of protein interactions by genetic vari... |
MARK AS OVER ANNOTATED |
Summary: Genetic variant effects on protein interactions.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: Large-scale binary interactome mapping.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:32296183
Apr 8. A reference map of the human binary protein interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... |
MARK AS OVER ANNOTATED |
Summary: Neurodegenerative disease protein interactome.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
|
|
GO:0005515
protein binding
|
IPI
PMID:32911434 A functionally defined high-density NRF2 interactome reveals... |
MODIFY |
Summary: NRF2 interactome study. ATF4-NRF2 cooperation in antioxidant response.
Reason: Functional interaction between ATF4 and NRF2.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:32911434
Aug 20. A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: Cell-specific interactome remodeling study.
Reason: Generic protein binding from HT study.
Supporting Evidence:
PMID:33961781
2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:9488481 ZIP kinase, a novel serine/threonine kinase which mediates a... |
MODIFY |
Summary: Interaction with ZIP kinase (DAPK3). ATF4 is phosphorylated by DAPK3.
Reason: This is a kinase-substrate interaction.
Proposed replacements:
protein kinase binding
Supporting Evidence:
PMID:9488481
ZIP kinase, a novel serine/threonine kinase which mediates apoptosis.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:16343488 Cooperative interaction of Zhangfei and ATF4 in transactivat... |
ACCEPT |
Summary: ATF4 can form homodimers through its leucine zipper domain.
Reason: ATF4 homodimerization is documented and functionally relevant for DNA binding.
Supporting Evidence:
PMID:16343488
2005 Dec 6. Cooperative interaction of Zhangfei and ATF4 in transactivation of the cyclic AMP response element.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
ACCEPT |
Summary: ATF4 homodimerization confirmed in systematic bZIP interaction study.
Reason: Confirms homodimerization capability.
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 can act as a transcriptional repressor in certain contexts, particularly for memory formation in neurons.
Reason: While ATF4 can repress transcription (e.g., long-term memory genes), its primary role is as a transcriptional activator in the ISR.
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 binds to CRE and CARE/AARE sequences in pol II-transcribed genes.
Reason: Core molecular function of ATF4.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is a pol II transcription factor.
Reason: Core molecular function.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 primarily functions as a transcriptional activator.
Reason: Core molecular function supported by experimental evidence.
|
|
GO:0005667
transcription regulator complex
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 forms complexes with other transcription factors.
Reason: ATF4 forms heterodimeric complexes with other bZIP factors.
|
|
GO:0007214
gamma-aminobutyric acid signaling pathway
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Based on rat ortholog. ATF4 interacts with GABA-B receptors in neurons.
Reason: This is a specialized neuronal function, not the core ISR role.
|
|
GO:0007623
circadian rhythm
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 can regulate circadian gene expression via CRE binding.
Reason: Circadian regulation is a secondary function.
|
|
GO:0008140
cAMP response element binding protein binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 heterodimerizes with CREB family members.
Reason: Documented interaction with CREB1 (PMID:12871976).
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0009636
response to toxic substance
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 is activated by various cellular stresses including toxic insults.
Reason: General stress response, not specific to toxicants.
|
|
GO:0010628
positive regulation of gene expression
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 positively regulates stress-responsive genes.
Reason: Core function as transcriptional activator.
|
|
GO:0030182
neuron differentiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Based on rat ortholog data.
Reason: Specialized developmental function, not core ISR role.
|
|
GO:0030282
bone mineralization
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 regulates osteoblast differentiation and bone formation.
Reason: Important physiological function but secondary to ISR role (PMID:15109498).
Supporting Evidence:
PMID:15109498
ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome.
|
|
GO:0030968
endoplasmic reticulum unfolded protein response
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is a key effector of the PERK branch of the UPR during ER stress.
Reason: Core function of ATF4 in the ISR/UPR (PMID:12871976, PMID:33384352).
Supporting Evidence:
PMID:33384352
QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis.
|
|
GO:0032590
dendrite membrane
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Based on rat ortholog. Relates to GABA-B receptor interaction in neurons.
Reason: Specialized neuronal localization.
|
|
GO:0032922
circadian regulation of gene expression
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 binds CRE elements in clock gene promoters.
Reason: Secondary function.
|
|
GO:0034198
cellular response to amino acid starvation
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is translationally induced during amino acid deprivation via GCN2-eIF2alpha pathway.
Reason: Core function - ATF4 is the central transcription factor activated during amino acid starvation (PMID:11960987).
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
|
|
GO:0034599
cellular response to oxidative stress
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ATF4 regulates antioxidant gene expression in response to oxidative stress.
Reason: ATF4 activates genes involved in redox homeostasis as part of the ISR.
|
|
GO:0034976
response to endoplasmic reticulum stress
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is the key transcription factor downstream of PERK during ER stress.
Reason: Core function (PMID:12871976, PMID:33384352).
|
|
GO:0035162
embryonic hemopoiesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Based on mouse knockout phenotype.
Reason: Developmental function, not core ISR role.
|
|
GO:0035497
cAMP response element binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 binds CRE sequences.
Reason: Core molecular function of ATF4 as a bZIP transcription factor.
|
|
GO:0036499
PERK-mediated unfolded protein response
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is the key transcription factor downstream of PERK.
Reason: Core function (PMID:31023583, PMID:12871976).
Supporting Evidence:
PMID:31023583
2019 Apr 22. ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
|
|
GO:0042789
mRNA transcription by RNA polymerase II
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 regulates pol II transcription.
Reason: Core function.
|
|
GO:0043267
negative regulation of potassium ion transport
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Based on rat ortholog. Specialized neuronal function.
Reason: Specialized neuronal function.
|
|
GO:0043525
positive regulation of neuron apoptotic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 with CHOP can promote neuronal apoptosis during prolonged stress.
Reason: Context-dependent pro-apoptotic function during chronic stress.
|
|
GO:0045667
regulation of osteoblast differentiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 is required for osteoblast differentiation.
Reason: Important developmental function but not core ISR role (PMID:15109498).
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 activates transcription of stress-responsive genes.
Reason: Core function.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 activates pol II-mediated transcription.
Reason: Core function.
|
|
GO:0046982
protein heterodimerization activity
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 heterodimerizes with other bZIP transcription factors via its leucine zipper domain.
Reason: Core molecular function for DNA binding (PMID:12871976, PMID:18940792).
Supporting Evidence:
PMID:18940792
2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.
|
|
GO:0048167
regulation of synaptic plasticity
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 acts as a memory suppressor in neurons.
Reason: Specialized neuronal function.
|
|
GO:0070059
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 with CHOP activates pro-apoptotic genes during prolonged ER stress.
Reason: Context-dependent function during chronic stress, not the primary adaptive role.
|
|
GO:0070309
lens fiber cell morphogenesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Based on mouse knockout phenotype.
Reason: Developmental function.
|
|
GO:0071456
cellular response to hypoxia
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is stabilized under hypoxia via reduced hydroxylation by PHD3.
Reason: ATF4 is regulated by hypoxia and contributes to hypoxic gene expression.
|
|
GO:0090575
RNA polymerase II transcription regulator complex
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 forms transcription factor complexes.
Reason: ATF4 forms heterodimeric complexes with other bZIP factors.
|
|
GO:0120163
negative regulation of cold-induced thermogenesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 suppresses thermogenic gene expression.
Reason: Specialized metabolic function.
|
|
GO:0140296
general transcription initiation factor binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 interacts with general transcription machinery.
Reason: Consistent with its function as a transcription factor.
|
|
GO:0140297
DNA-binding transcription factor binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 interacts with other transcription factors.
Reason: ATF4 heterodimerizes with other bZIP transcription factors.
|
|
GO:0140467
integrated stress response signaling
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is THE central transcription factor of the ISR.
Reason: Core function - ATF4 is the master transcription factor effector of the ISR (PMID:32132707).
Supporting Evidence:
PMID:32132707
Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
|
|
GO:1903377
negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF4 can be protective against oxidative stress in neurons.
Reason: Context-dependent neuroprotective function.
|
|
GO:1990253
cellular response to leucine starvation
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 is induced by leucine starvation via GCN2.
Reason: Core function - amino acid sensing is a primary trigger of ATF4 induction.
|
|
GO:1990589
ATF4-CREB1 transcription factor complex
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate of IBA annotation.
Reason: ATF4-CREB1 complex formation is documented.
|
|
GO:1990590
ATF1-ATF4 transcription factor complex
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate of IBA annotation.
Reason: ATF4-ATF1 complex formation is documented.
|
|
GO:1990737
response to manganese-induced endoplasmic reticulum stress
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Specific stressor that activates ER stress and ATF4.
Reason: Specific toxic stressor response.
|
|
GO:1990841
promoter-specific chromatin binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF4 binds to specific promoter sequences.
Reason: Core molecular function.
|
|
GO:0005654
nucleoplasm
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: Nucleoplasmic localization confirmed by immunofluorescence.
Reason: Consistent with nuclear transcription factor function.
|
|
GO:0005634
nucleus
|
NAS
PMID:12871976 Induction of Grp78/BiP by translational block: activation of... |
ACCEPT |
Summary: Nuclear localization discussed in study.
Reason: Consistent with transcription factor function.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0005634
nucleus
|
NAS
PMID:20102225 Identification of bZIP interaction partners of viral protein... |
ACCEPT |
Summary: Nuclear localization in bZIP interaction study.
Reason: Consistent with transcription factor function.
Supporting Evidence:
PMID:20102225
Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
|
|
GO:0005634
nucleus
|
NAS
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
ACCEPT |
Summary: Nuclear localization in bZIP network study.
Reason: Consistent with transcription factor function.
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0005634
nucleus
|
NAS
PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif... |
ACCEPT |
Summary: Nuclear localization discussed.
Reason: Consistent with transcription factor function.
Supporting Evidence:
PMID:28186491
Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
NAS
PMID:20102225 Identification of bZIP interaction partners of viral protein... |
ACCEPT |
Summary: Transcriptional regulation discussed.
Reason: Core function.
Supporting Evidence:
PMID:20102225
Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
NAS
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
ACCEPT |
Summary: Transcriptional regulation discussed.
Reason: Core function.
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
NAS
PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif... |
ACCEPT |
Summary: Transcriptional regulation discussed.
Reason: Core function.
Supporting Evidence:
PMID:28186491
Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:16343488 Cooperative interaction of Zhangfei and ATF4 in transactivat... |
ACCEPT |
Summary: ATF4 with Zhangfei cooperatively activates CRE-driven transcription.
Reason: Direct experimental evidence for transcriptional activation.
Supporting Evidence:
PMID:16343488
2005 Dec 6. Cooperative interaction of Zhangfei and ATF4 in transactivation of the cyclic AMP response element.
|
|
GO:0140467
integrated stress response signaling
|
NAS
PMID:28566324 Multi-omics analysis identifies ATF4 as a key regulator of t... |
ACCEPT |
Summary: ATF4 as key regulator of mitochondrial stress response.
Reason: Core function in ISR.
Supporting Evidence:
PMID:28566324
2017 May 31. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IDA
PMID:31023583 ER and Nutrient Stress Promote Assembly of Respiratory Chain... |
ACCEPT |
Summary: ATF4 transcription factor activity demonstrated in PERK-eIF2alpha axis study.
Reason: Core molecular function.
Supporting Evidence:
PMID:31023583
2019 Apr 22. ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
|
|
GO:0036499
PERK-mediated unfolded protein response
|
IDA
PMID:31023583 ER and Nutrient Stress Promote Assembly of Respiratory Chain... |
ACCEPT |
Summary: ATF4 mediates PERK-dependent transcription.
Reason: Core function.
Supporting Evidence:
PMID:31023583
2019 Apr 22. ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IDA
PMID:23123191 Functional interaction of protein kinase CK2 and activating ... |
ACCEPT |
Summary: ATF4 transcription factor activity demonstrated, regulated by CK2 phosphorylation.
Reason: Core molecular function.
Supporting Evidence:
PMID:23123191
Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IDA
PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... |
ACCEPT |
Summary: ATF4 transcription factor activity in mitochondrial stress response.
Reason: Core molecular function.
Supporting Evidence:
PMID:32132707
Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
|
|
GO:0140468
HRI-mediated signaling
|
IDA
PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... |
ACCEPT |
Summary: ATF4 is downstream of HRI in mitochondrial stress signaling.
Reason: Core function - ATF4 is activated by HRI during mitochondrial stress via DELE1.
Supporting Evidence:
PMID:32132706
Mar 4. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.
|
|
GO:0034599
cellular response to oxidative stress
|
IMP
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
ACCEPT |
Summary: ATF4 mediates transcriptional response to oxidative stress in neurons.
Reason: Core function in stress response.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0034976
response to endoplasmic reticulum stress
|
IDA
PMID:12871976 Induction of Grp78/BiP by translational block: activation of... |
ACCEPT |
Summary: ATF4 activates GRP78/BiP promoter during ER stress.
Reason: Core function.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0034976
response to endoplasmic reticulum stress
|
IMP
PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... |
ACCEPT |
Summary: ATF4 transcriptionally regulates parkin during ER stress.
Reason: Core function.
Supporting Evidence:
PMID:21113145
Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:12871976 Induction of Grp78/BiP by translational block: activation of... |
ACCEPT |
Summary: ATF4 activates GRP78/BiP transcription.
Reason: Core function.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IMP
PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... |
ACCEPT |
Summary: ATF4 activates parkin transcription.
Reason: Core function.
Supporting Evidence:
PMID:21113145
Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
ISS
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
ACCEPT |
Summary: Based on rat ortholog study of neuroprotection.
Reason: Consistent with core function.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IMP
PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas... |
ACCEPT |
Summary: ATF4 activates DR5 transcription during ER stress.
Reason: Core function.
Supporting Evidence:
PMID:24939851
2014 Jun 17. Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib.
|
|
GO:0034599
cellular response to oxidative stress
|
IMP
PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... |
ACCEPT |
Summary: ATF4 mediates oxidative stress response.
Reason: Core function.
Supporting Evidence:
PMID:21113145
Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.
|
|
GO:1903377
negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway
|
IGI
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
KEEP AS NON CORE |
Summary: ATF4 protects neurons against oxidative stress-induced apoptosis.
Reason: Specialized neuroprotective function.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
TAS
PMID:14685163 Roles of CHOP/GADD153 in endoplasmic reticulum stress. |
ACCEPT |
Summary: Review discusses ATF4 transcriptional activation with CHOP.
Reason: Core function.
Supporting Evidence:
PMID:14685163
Roles of CHOP/GADD153 in endoplasmic reticulum stress.
|
|
GO:1990253
cellular response to leucine starvation
|
IDA
PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... |
ACCEPT |
Summary: ATF4 binds chromatin during amino acid starvation.
Reason: Core function in amino acid sensing.
Supporting Evidence:
PMID:17267404
ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation.
|
|
GO:1990841
promoter-specific chromatin binding
|
IDA
PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... |
ACCEPT |
Summary: ATF4 chromatin binding demonstrated by ChIP.
Reason: Core molecular function.
Supporting Evidence:
PMID:17267404
ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation.
|
|
GO:0034976
response to endoplasmic reticulum stress
|
IDA
PMID:33384352 QRICH1 dictates the outcome of ER stress through transcripti... |
ACCEPT |
Summary: ATF4 cooperates with QRICH1 in ER stress response.
Reason: Core function.
Supporting Evidence:
PMID:33384352
QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis.
|
|
GO:0140467
integrated stress response signaling
|
IDA
PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... |
ACCEPT |
Summary: ATF4 is the key effector of the ISR.
Reason: Core function.
Supporting Evidence:
PMID:32132707
Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
|
|
GO:0140468
HRI-mediated signaling
|
IDA
PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... |
ACCEPT |
Summary: ATF4 downstream of HRI in mitochondrial stress.
Reason: Core function.
Supporting Evidence:
PMID:32132707
Mar 4. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
|
|
GO:1990837
sequence-specific double-stranded DNA binding
|
IDA
PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... |
ACCEPT |
Summary: ATF4 DNA binding specificity characterized, including methylation sensitivity.
Reason: Core molecular function.
Supporting Evidence:
PMID:28473536
Impact of cytosine methylation on DNA binding specificities of human transcription factors.
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4 can repress transcription in certain contexts.
Reason: ATF4 primarily activates transcription; repression is context-dependent.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IDA
PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... |
ACCEPT |
Summary: ATF4 transcription factor activity in nutrient sensing.
Reason: Core molecular function.
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IDA
PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of os... |
ACCEPT |
Summary: ATF4 transcription factor activity in osteoblast differentiation.
Reason: Core molecular function.
Supporting Evidence:
PMID:15109498
ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome.
|
|
GO:0005515
protein binding
|
IPI
PMID:23123191 Functional interaction of protein kinase CK2 and activating ... |
MODIFY |
Summary: ATF4 interacts with CK2 as a substrate.
Reason: This is a kinase-substrate interaction.
Proposed replacements:
protein kinase binding
Supporting Evidence:
PMID:23123191
Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response.
|
|
GO:0005634
nucleus
|
IDA
PMID:23123191 Functional interaction of protein kinase CK2 and activating ... |
ACCEPT |
Summary: Nuclear localization of ATF4-CK2 interaction.
Reason: Core localization.
Supporting Evidence:
PMID:23123191
Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response.
|
|
GO:0008140
cAMP response element binding protein binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 interacts with CREB family members.
Reason: Documented interaction.
|
|
GO:0030282
bone mineralization
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4 regulates bone mineralization via osteoblast function.
Reason: Physiological function but not core ISR role.
|
|
GO:0030968
endoplasmic reticulum unfolded protein response
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 is a key UPR effector.
Reason: Core function.
|
|
GO:0031667
response to nutrient levels
|
IDA
PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... |
ACCEPT |
Summary: ATF4 mediates transcriptional response to nutrient deprivation.
Reason: Core function in nutrient sensing.
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
|
|
GO:0034599
cellular response to oxidative stress
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 mediates oxidative stress response.
Reason: Core function.
|
|
GO:0035162
embryonic hemopoiesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Based on mouse knockout phenotype.
Reason: Developmental function.
|
|
GO:0036499
PERK-mediated unfolded protein response
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 downstream of PERK.
Reason: Core function.
|
|
GO:0045667
regulation of osteoblast differentiation
|
IDA
PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of os... |
KEEP AS NON CORE |
Summary: ATF4 is required for osteoblast differentiation.
Reason: Important but not core ISR function.
Supporting Evidence:
PMID:15109498
ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... |
ACCEPT |
Summary: ATF4 activates ASNS transcription.
Reason: Core function.
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:15109498 ATF4 is a substrate of RSK2 and an essential regulator of os... |
ACCEPT |
Summary: ATF4 activates osteoblast gene transcription.
Reason: Core function.
Supporting Evidence:
PMID:15109498
ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:23123191 Functional interaction of protein kinase CK2 and activating ... |
ACCEPT |
Summary: ATF4 transcriptional activity regulated by CK2.
Reason: Core function.
Supporting Evidence:
PMID:23123191
Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response.
|
|
GO:0046982
protein heterodimerization activity
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 heterodimerizes with bZIP partners.
Reason: Core molecular function.
|
|
GO:0048167
regulation of synaptic plasticity
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4 regulates memory-related genes.
Reason: Specialized neuronal function.
|
|
GO:0070309
lens fiber cell morphogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Based on mouse knockout phenotype.
Reason: Developmental function.
|
|
GO:0070982
L-asparagine metabolic process
|
IDA
PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... |
ACCEPT |
Summary: ATF4 activates asparagine synthetase (ASNS) gene transcription.
Reason: Core target gene regulation.
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
|
|
GO:0010628
positive regulation of gene expression
|
IMP
PMID:16445384 Characterization of the amino acid response element within t... |
ACCEPT |
Summary: ATF4 regulates SNAT2 expression.
Reason: Core function in amino acid transporter regulation.
Supporting Evidence:
PMID:16445384
Characterization of the amino acid response element within the human sodium-coupled neutral amino acid transporter 2 (SNAT2) System A transporter gene.
|
|
GO:0003677
DNA binding
|
IDA
PMID:15911876 FIAT represses ATF4-mediated transcription to regulate bone ... |
ACCEPT |
Summary: ATF4 DNA binding activity demonstrated.
Reason: Core molecular function.
Supporting Evidence:
PMID:15911876
FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice.
|
|
GO:0000785
chromatin
|
ISA
GO_REF:0000113 |
ACCEPT |
Summary: ATF4 binds chromatin as a transcription factor.
Reason: Consistent with transcription factor function.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
ISA
GO_REF:0000113 |
ACCEPT |
Summary: ATF4 is a pol II transcription factor.
Reason: Core molecular function.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IDA
PMID:12871976 Induction of Grp78/BiP by translational block: activation of... |
ACCEPT |
Summary: ATF4 transcription factor activity demonstrated.
Reason: Core molecular function.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0120163
negative regulation of cold-induced thermogenesis
|
ISS
PMID:22980225 Effects of ATF4 on PGC1α expression in brown adipose tissue ... |
KEEP AS NON CORE |
Summary: ATF4 suppresses thermogenic gene expression.
Reason: Specialized metabolic function.
Supporting Evidence:
PMID:22980225
2012 Sep 11. Effects of ATF4 on PGC1α expression in brown adipose tissue and metabolic responses to cold stress.
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 binds CRE sequences.
Reason: Core molecular function.
|
|
GO:0005813
centrosome
|
IDA
PMID:20873783 Characterization of hNek6 interactome reveals an important r... |
KEEP AS NON CORE |
Summary: ATF4 localizes to centrosome with NEK6.
Reason: Non-canonical localization, not central to ISR function.
Supporting Evidence:
PMID:20873783
Oct 22. Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome.
|
|
GO:0019901
protein kinase binding
|
IPI
PMID:20873783 Characterization of hNek6 interactome reveals an important r... |
ACCEPT |
Summary: ATF4 interacts with NEK6 kinase.
Reason: Documented kinase interaction.
Supporting Evidence:
PMID:20873783
Oct 22. Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome.
|
|
GO:0032991
protein-containing complex
|
IDA
PMID:20873783 Characterization of hNek6 interactome reveals an important r... |
ACCEPT |
Summary: ATF4 forms protein complexes.
Reason: Consistent with bZIP dimerization.
Supporting Evidence:
PMID:20873783
Oct 22. Characterization of hNek6 interactome reveals an important role for its short N-terminal domain and colocalization with proteins at the centrosome.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9796061 |
ACCEPT |
Summary: ATF4 is synthesized in the cytosol.
Reason: ATF4 is translated in the cytoplasm.
|
|
GO:0005634
nucleus
|
IDA
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
ACCEPT |
Summary: Nuclear localization in Parkinson's disease model.
Reason: Core localization.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0032057
negative regulation of translational initiation in response to stress
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4 is part of the translation regulation pathway via ISR.
Reason: ATF4 is a consequence of translation regulation, not a direct regulator of translation initiation.
|
|
GO:0034644
cellular response to UV
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 is induced by UV stress.
Reason: Part of general stress response.
|
|
GO:0034198
cellular response to amino acid starvation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 is induced by amino acid starvation.
Reason: Core function.
|
|
GO:0042789
mRNA transcription by RNA polymerase II
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 regulates pol II transcription.
Reason: Core function.
|
|
GO:0036499
PERK-mediated unfolded protein response
|
TAS
PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... |
ACCEPT |
Summary: ATF4 downstream of PERK discussed in review.
Reason: Core function.
Supporting Evidence:
PMID:22934019
The endoplasmic reticulum stress response in aging and age-related diseases.
|
|
GO:0034976
response to endoplasmic reticulum stress
|
IMP
PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas... |
ACCEPT |
Summary: ATF4 mediates ER stress response.
Reason: Core function.
Supporting Evidence:
PMID:24939851
2014 Jun 17. Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib.
|
|
GO:0036499
PERK-mediated unfolded protein response
|
TAS
PMID:22013210 The unfolded protein response: integrating stress signals th... |
ACCEPT |
Summary: ATF4 downstream of PERK in UPR.
Reason: Core function.
Supporting Evidence:
PMID:22013210
The unfolded protein response: integrating stress signals through the stress sensor IRE1α.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IDA
PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... |
ACCEPT |
Summary: ATF4 transcription factor activity with CHOP.
Reason: Core molecular function.
Supporting Evidence:
PMID:11478948
The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).
|
|
GO:0043522
leucine zipper domain binding
|
IDA
PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... |
ACCEPT |
Summary: ATF4 interacts with CHOP via leucine zipper.
Reason: Core molecular function for bZIP heterodimerization.
Supporting Evidence:
PMID:11478948
The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).
|
|
GO:0061629
RNA polymerase II-specific DNA-binding transcription factor binding
|
IPI
PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... |
ACCEPT |
Summary: ATF4 interacts with CHOP transcription factor.
Reason: Core molecular function.
Supporting Evidence:
PMID:11478948
The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).
|
|
GO:1990617
CHOP-ATF4 complex
|
IDA
PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... |
ACCEPT |
Summary: ATF4-CHOP complex formation demonstrated.
Reason: Important transcription factor complex in stress response.
Supporting Evidence:
PMID:11478948
The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).
|
|
GO:0005634
nucleus
|
IDA
PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... |
ACCEPT |
Summary: Nuclear localization with CHOP.
Reason: Core localization.
Supporting Evidence:
PMID:11478948
The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:11478948 The cAMP response element binding protein-2 (CREB-2) can int... |
ACCEPT |
Summary: ATF4-CHOP activates transcription.
Reason: Core function.
Supporting Evidence:
PMID:11478948
The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:15775988 TRB3, a novel ER stress-inducible gene, is induced via ATF4-... |
ACCEPT |
Summary: ATF4-CHOP activates TRB3 transcription.
Reason: Core function.
Supporting Evidence:
PMID:15775988
Mar 10. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... |
ACCEPT |
Summary: ATF4 activates transcription, regulated by CHOP.
Reason: Core function.
Supporting Evidence:
PMID:18940792
2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.
|
|
GO:1990617
CHOP-ATF4 complex
|
NAS
PMID:15775988 TRB3, a novel ER stress-inducible gene, is induced via ATF4-... |
ACCEPT |
Summary: ATF4-CHOP complex discussed.
Reason: Important complex.
Supporting Evidence:
PMID:15775988
Mar 10. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.
|
|
GO:1990617
CHOP-ATF4 complex
|
IPI
PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... |
ACCEPT |
Summary: ATF4-CHOP interaction demonstrated.
Reason: Important complex.
Supporting Evidence:
PMID:18940792
2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.
|
|
GO:1990589
ATF4-CREB1 transcription factor complex
|
IDA
PMID:12871976 Induction of Grp78/BiP by translational block: activation of... |
ACCEPT |
Summary: ATF4-CREB1 complex demonstrated.
Reason: Core transcription factor complex.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:1990590
ATF1-ATF4 transcription factor complex
|
IDA
PMID:12871976 Induction of Grp78/BiP by translational block: activation of... |
ACCEPT |
Summary: ATF4-ATF1 complex demonstrated.
Reason: Core transcription factor complex.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0000976
transcription cis-regulatory region binding
|
IDA
PMID:12871976 Induction of Grp78/BiP by translational block: activation of... |
ACCEPT |
Summary: ATF4 binds to ATF/CRE regulatory sequences.
Reason: Core molecular function.
Supporting Evidence:
PMID:12871976
2003 Jul 18. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements.
|
|
GO:0010575
positive regulation of vascular endothelial growth factor production
|
IMP
PMID:22915762 The unfolded protein response induces the angiogenic switch ... |
KEEP AS NON CORE |
Summary: ATF4 induces VEGF during ER stress.
Reason: Context-dependent angiogenic function.
Supporting Evidence:
PMID:22915762
Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway.
|
|
GO:0042149
cellular response to glucose starvation
|
IMP
PMID:22915762 The unfolded protein response induces the angiogenic switch ... |
ACCEPT |
Summary: ATF4 mediates glucose starvation response.
Reason: Part of nutrient stress response.
Supporting Evidence:
PMID:22915762
Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway.
|
|
GO:0043565
sequence-specific DNA binding
|
IDA
PMID:22915762 The unfolded protein response induces the angiogenic switch ... |
ACCEPT |
Summary: ATF4 DNA binding activity.
Reason: Core molecular function.
Supporting Evidence:
PMID:22915762
Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway.
|
|
GO:0045943
positive regulation of transcription by RNA polymerase I
|
IMP
PMID:22915762 The unfolded protein response induces the angiogenic switch ... |
UNDECIDED |
Summary: ATF4 may regulate pol I transcription.
Reason: ATF4 is primarily a pol II transcription factor. Pol I regulation is atypical and needs verification.
Supporting Evidence:
PMID:22915762
Epub 2012 Aug 20. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway.
|
|
GO:0000976
transcription cis-regulatory region binding
|
IDA
PMID:21113145 Parkin is transcriptionally regulated by ATF4: evidence for ... |
ACCEPT |
Summary: ATF4 binds parkin promoter.
Reason: Core molecular function.
Supporting Evidence:
PMID:21113145
Nov 26. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress.
|
|
GO:0000976
transcription cis-regulatory region binding
|
TAS
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
ACCEPT |
Summary: ATF4 cis-regulatory binding discussed.
Reason: Core molecular function.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0005737
cytoplasm
|
IDA
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
ACCEPT |
Summary: Cytoplasmic ATF4 in neurons.
Reason: ATF4 can be cytoplasmic before stress-induced nuclear translocation.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0034399
nuclear periphery
|
IDA
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
KEEP AS NON CORE |
Summary: ATF4 at nuclear periphery in neurons.
Reason: Specialized neuronal localization.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0043005
neuron projection
|
IDA
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
KEEP AS NON CORE |
Summary: ATF4 in neuron projections.
Reason: Specialized neuronal localization.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0043065
positive regulation of apoptotic process
|
TAS
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
KEEP AS NON CORE |
Summary: ATF4 can promote apoptosis during stress.
Reason: Context-dependent pro-apoptotic function.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:1990037
Lewy body core
|
IDA
PMID:23392669 ATF4 protects against neuronal death in cellular Parkinson's... |
KEEP AS NON CORE |
Summary: ATF4 found in Lewy bodies in Parkinson's disease.
Reason: Pathological localization in neurodegeneration.
Supporting Evidence:
PMID:23392669
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin.
|
|
GO:0032922
circadian regulation of gene expression
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4 regulates circadian genes.
Reason: Secondary function.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9635804 |
ACCEPT |
Summary: ATF4 nucleoplasmic localization in Reactome pathway.
Reason: Core localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9635892 |
ACCEPT |
Summary: ATF4 nucleoplasmic localization.
Reason: Core localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9635936 |
ACCEPT |
Summary: ATF4 nucleoplasmic localization.
Reason: Core localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9653893 |
ACCEPT |
Summary: ATF4 nucleoplasmic localization.
Reason: Core localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9761815 |
ACCEPT |
Summary: ATF4 nucleoplasmic localization.
Reason: Core localization.
|
|
GO:0003677
DNA binding
|
IDA
PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... |
ACCEPT |
Summary: ATF4 DNA binding demonstrated.
Reason: Core molecular function.
Supporting Evidence:
PMID:18940792
2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.
|
|
GO:0005515
protein binding
|
IPI
PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... |
MODIFY |
Summary: ATF4 interacts with CHOP.
Reason: This is a specific bZIP-bZIP interaction.
Proposed replacements:
leucine zipper domain binding
Supporting Evidence:
PMID:18940792
2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.
|
|
GO:0043525
positive regulation of neuron apoptotic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4-CHOP can promote neuronal apoptosis.
Reason: Context-dependent, not core function.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IDA
PMID:18940792 C/EBP homology protein (CHOP) interacts with activating tran... |
ACCEPT |
Summary: ATF4 activates transcription.
Reason: Core function.
Supporting Evidence:
PMID:18940792
2008 Oct 21. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.
|
|
GO:0070059
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4-CHOP activate apoptotic pathway during prolonged ER stress.
Reason: Context-dependent, chronic stress response.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IDA
PMID:15775988 TRB3, a novel ER stress-inducible gene, is induced via ATF4-... |
ACCEPT |
Summary: ATF4-CHOP activate TRB3 transcription.
Reason: Core function.
Supporting Evidence:
PMID:15775988
Mar 10. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.
|
|
GO:0034976
response to endoplasmic reticulum stress
|
IDA
PMID:19061639 Role of SERCA1 truncated isoform in the proapoptotic calcium... |
ACCEPT |
Summary: ATF4 in ER stress response.
Reason: Core function.
Supporting Evidence:
PMID:19061639
Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress.
|
|
GO:0005515
protein binding
|
IPI
PMID:16682973 The centrosomal protein nephrocystin-6 is mutated in Joubert... |
ACCEPT |
Summary: ATF4 interacts with CEP290/nephrocystin-6.
Reason: Functionally relevant interaction affecting ATF4 activity.
Supporting Evidence:
PMID:16682973
The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.
|
|
GO:0005634
nucleus
|
IDA
PMID:16682973 The centrosomal protein nephrocystin-6 is mutated in Joubert... |
ACCEPT |
Summary: Nuclear localization with CEP290.
Reason: Core localization.
Supporting Evidence:
PMID:16682973
The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.
|
|
GO:0005515
protein binding
|
IPI
PMID:15677469 Mitosin/CENP-F as a negative regulator of activating transcr... |
KEEP AS NON CORE |
Summary: ATF4 interacts with mitosin/CENP-F.
Reason: Interaction affecting ATF4 regulation but not core function.
Supporting Evidence:
PMID:15677469
2005 Jan 26. Mitosin/CENP-F as a negative regulator of activating transcription factor-4.
|
|
GO:0003677
DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 DNA binding.
Reason: Core molecular function.
|
|
GO:0003677
DNA binding
|
IDA
PMID:15788408 The oxidative stressor arsenite activates vascular endotheli... |
ACCEPT |
Summary: ATF4 DNA binding in arsenite response.
Reason: Core molecular function.
Supporting Evidence:
PMID:15788408
2005 Mar 23. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism.
|
|
GO:0003700
DNA-binding transcription factor activity
|
TAS
PMID:12689582 All roads lead to ATF4. |
ACCEPT |
Summary: Review of ATF4 as transcription factor.
Reason: Core molecular function.
Supporting Evidence:
PMID:12689582
All roads lead to ATF4.
|
|
GO:0005634
nucleus
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Nuclear localization.
Reason: Core localization.
|
|
GO:0005737
cytoplasm
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Cytoplasmic localization.
Reason: ATF4 is translated in cytoplasm.
|
|
GO:0006094
gluconeogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ATF4 regulates gluconeogenic genes.
Reason: Metabolic function, not core ISR role.
|
|
GO:0006355
regulation of DNA-templated transcription
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 regulates transcription.
Reason: Core function.
|
|
GO:0006366
transcription by RNA polymerase II
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 in pol II transcription.
Reason: Core function.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 activates transcription.
Reason: Core function.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IMP
PMID:11960987 ATF4 is a mediator of the nutrient-sensing response pathway ... |
ACCEPT |
Summary: ATF4 activates ASNS transcription.
Reason: Core function.
Supporting Evidence:
PMID:11960987
2002 Apr 17. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
NAS
PMID:9190894 Functional interaction of the HTLV-1 transactivator Tax with... |
ACCEPT |
Summary: ATF4 with HTLV-1 Tax in transcription.
Reason: Core function.
Supporting Evidence:
PMID:9190894
Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4).
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ATF4 activates pol II transcription.
Reason: Core function.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IMP
PMID:15788408 The oxidative stressor arsenite activates vascular endotheli... |
ACCEPT |
Summary: ATF4 activates VEGF transcription.
Reason: Core function.
Supporting Evidence:
PMID:15788408
2005 Mar 23. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism.
|
Q: What determines whether ATF4 promotes cell survival (adaptive ISR) versus cell death (terminal UPR/apoptosis)?
Q: How do different bZIP dimerization partners affect ATF4 target gene specificity?
Q: What is the significance of ATF4 localization to the centrosome and its interaction with NEK6?
Experiment: ChIP-seq comparing ATF4 chromatin binding with different stress conditions (ER stress vs amino acid starvation vs mitochondrial stress) to define stress-specific target genes
Hypothesis: Different stressors activate distinct ATF4 target gene programs
Experiment: Time-course proteomics following ATF4 induction to distinguish early adaptive targets from late pro-apoptotic targets
Hypothesis: Temporal dynamics of ATF4 activity determines cell fate
Experiment: CRISPR screens to identify ATF4-dependent genes essential for survival during different stress conditions
Hypothesis: Specific ATF4 target genes are required for stress adaptation
provider: cyberian
model: deep-research
cached: false
start_time: '2026-01-15T17:06:50.839646'
end_time: '2026-01-15T17:25:50.516744'
duration_seconds: 1139.68
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: ATF4
gene_symbol: ATF4
uniprot_accession: P18848
protein_description: 'RecName: Full=Cyclic AMP-dependent transcription factor ATF-4
{ECO:0000305}; Short=cAMP-dependent transcription factor ATF-4 {ECO:0000305};
AltName: Full=Activating transcription factor 4 {ECO:0000303|PubMed:2516827};
AltName: Full=Cyclic AMP-responsive element-binding protein 2 {ECO:0000303|PubMed:1534408};
Short=CREB-2 {ECO:0000303|PubMed:1534408}; Short=cAMP-responsive element-binding
protein 2 {ECO:0000303|PubMed:1534408}; AltName: Full=Tax-responsive enhancer
element-binding protein 67 {ECO:0000303|PubMed:1847461}; Short=TaxREB67 {ECO:0000303|PubMed:1847461};'
gene_info: Name=ATF4 {ECO:0000303|PubMed:2516827, ECO:0000312|HGNC:HGNC:786}; Synonyms=CREB2
{ECO:0000303|PubMed:1534408}, TXREB {ECO:0000303|PubMed:1847461};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the bZIP family. .
protein_domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_1 (PF00170)
provider_config:
timeout: 1800
max_retries: 3
parameters:
allowed_domains: []
agent_type: claude
port: 3284
skip_permissions: true
citation_count: 10
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATF4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene ATF4 (gene ID: ATF4, UniProt: P18848) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
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Activating Transcription Factor 4 (ATF4), also known as CREB-2 (cAMP response element-binding protein 2) or TaxREB67, is a basic leucine zipper (bZIP) transcription factor that serves as a master regulator of cellular stress responses in eukaryotes. ATF4 (UniProt: P18848) is encoded by the ATF4 gene on human chromosome 22q13.1 and produces a 351 amino acid protein that functions as a central effector of the Integrated Stress Response (ISR) [pakos-zebrucka-2016-isr-review-summary]. Unlike typical transcription factors that are primarily regulated at the transcriptional level, ATF4 is predominantly controlled through a sophisticated translational mechanism involving upstream open reading frames (uORFs) that enable preferential translation under stress conditions when global protein synthesis is suppressed [young-wek-2016-uorf-summary].
ATF4 belongs to the ATF/CREB family of transcription factors, which are characterized by their ability to bind cAMP response elements (CREs) in target gene promoters. The protein was first molecularly cloned in 1992 by Karpinski and colleagues from a Jurkat T-cell cDNA library, where it was initially characterized as a transcriptional repressor of CRE-dependent transcription [karpinski-1992-creb2-cloning-summary]. Subsequent research has revealed that ATF4 can function as both an activator and repressor of transcription depending on its dimerization partners and post-translational modifications. ATF4 plays pivotal roles in amino acid metabolism, oxidative stress response, autophagy, apoptosis, and development, making it a critical nexus point in cellular adaptation to environmental challenges [neill-2023-atf4-review-summary].
The 351 amino acid ATF4 protein is organized into two major functional domains: an N-terminal transactivation domain (TAD, residues 1-275) and a C-terminal basic leucine zipper (bZIP) domain (residues 276-351). The N-terminal domain, which includes a p300 interaction site, functions as a transcriptional activation domain and is also implicated in regulating protein stability. Structurally, the N-terminal transactivation domain is intrinsically disordered, a feature that allows for flexible interactions with multiple binding partners and regulatory proteins.
The C-terminal bZIP domain is essential for ATF4's DNA binding and dimerization functions. This domain comprises three distinct regions: a DNA binding region (DB, residues 280-301), a leucine zipper region (LZ, residues 306-340), and a secondary basic motif (B2, residues 341-351) that is shared exclusively with its closest paralogue, ATF5. The leucine zipper region contains the characteristic heptad repeat with leucine residues at every seventh position, enabling homo- and heterodimerization through coiled-coil interactions. Structural studies using proteolysis, electrophoretic mobility shift assays, circular dichroism, and NMR have demonstrated that the bZIP domain of ATF4 exists as a disordered monomer in solution but forms a homodimer upon binding to target DNA sequences.
ATF4 binds to the cAMP response element (CRE) with the consensus sequence 5'-GTGACGT[AC][AG]-3'. Notably, ATF4 binds to asymmetric CREs as a heterodimer and to palindromic CREs as a homodimer. A crystal structure of the C/EBPβ-ATF4 bZIP heterodimer revealed that the heterodimer forms an asymmetric coiled-coil structure. Intriguingly, even in the absence of DNA, the basic region of ATF4 forms a continuous alpha-helix, while the basic region of C/EBPβ remains disordered, suggesting a structural asymmetry that may contribute to target gene specificity.
The selection of target genes regulated by ATF4 is critically dependent on its dimerization partners. Neill and Masson catalogued 14 direct dimerization partners for ATF4, predominantly bZIP transcription factors including CEBPB, CEBPG, JUN, and DDIT3/CHOP [neill-2023-atf4-review-summary]. Work in mice has identified CEBPG as the main ATF4 heterodimerization partner for inducing stress-responsive genes. ATF4 can also heterodimerize with JUN, FOS, and FRA1 to bind CRE sequences, or with CHOP to regulate a distinct subset of pro-apoptotic genes. These partnerships function as "combinatorial switches" that select target gene subsets depending on the cellular context and nature of the stress stimulus.
One of the most distinctive features of ATF4 regulation is the sophisticated mechanism by which its translation is controlled. Although ATF4 mRNA is constitutively expressed in cells, ATF4 protein levels are kept low under normal conditions through a translational repression mechanism involving upstream open reading frames (uORFs) in the 5' untranslated region [young-wek-2016-uorf-summary]. This mechanism enables a paradoxical increase in ATF4 translation precisely when global protein synthesis is suppressed during cellular stress.
The 5' UTR of ATF4 mRNA contains two uORFs in strong Kozak sequences: uORF1 is only 3 codons long, while uORF2 is 59 amino acids long and overlaps out-of-frame with the main ATF4 coding sequence. Under normal non-stress conditions, when the eukaryotic initiation factor 2 (eIF2) ternary complex (eIF2-GTP-Met-tRNAi) is abundant, ribosomes translate the short uORF1, remain attached to the mRNA, resume scanning downstream, and rapidly reacquire the ternary complex before encountering uORF2. Translation of uORF2 then prevents initiation at the ATF4 main open reading frame because of the out-of-frame overlap.
During cellular stress, the picture changes dramatically. Stress signals activate one of four eIF2α kinases (PERK, GCN2, PKR, or HRI), leading to phosphorylation of eIF2α at serine 51. Phosphorylated eIF2α binds more strongly to eIF2B, inhibiting its guanine nucleotide exchange factor (GEF) function and reducing the available pool of eIF2 ternary complex. Under these conditions, ribosomes that translate uORF1 and resume scanning take longer to reacquire the ternary complex. By the time they do so, many have bypassed uORF2, allowing them to instead reinitiate translation at the ATF4 main coding sequence. This "delayed reinitiation" mechanism elegantly couples stress-induced eIF2α phosphorylation to preferential ATF4 translation [young-wek-2016-uorf-summary].
Recent studies have identified additional regulators of this translational mechanism. The noncanonical initiation factors eIF2D and DENR are critical for ATF4 induction, with loss of these factors in Drosophila resulting in increased vulnerability to amino acid deprivation, susceptibility to retinal degeneration caused by ER stress, and developmental defects similar to ATF4 mutants.
The translational control mechanism governing ATF4 expression is remarkably conserved across eukaryotes, reflecting its fundamental importance in cellular stress responses. In the budding yeast Saccharomyces cerevisiae, the transcription factor GCN4 serves as the functional homolog of mammalian ATF4, orchestrating the general amino acid control (GAAC) response to amino acid starvation [hinnebusch-2005-gcn4-review-summary]. Like ATF4, GCN4 is a bZIP transcription factor whose translation is regulated by upstream open reading frames in response to eIF2α phosphorylation. GCN4 contains four short uORFs in its 5' leader (compared to two in ATF4), but the fundamental mechanism of delayed reinitiation is conserved: under amino acid sufficiency, the uORFs repress GCN4 translation, while during starvation, reduced eIF2 ternary complex availability allows ribosomes to bypass the inhibitory uORFs and translate GCN4.
The eIF2α/GCN2 signaling pathway upstream of this translational control is extremely well conserved, with GCN2 protein kinases phosphorylating eIF2α in response to uncharged tRNA accumulation across fungi, mammals, plants, and parasitic organisms including Plasmodium and Toxoplasma. GCN4 regulates the expression of more than 500 genes in yeast, including nearly all genes encoding amino acid biosynthetic enzymes. Interestingly, despite the conservation of the signaling pathway, the downstream transcription factors themselves have diverged considerably. GCN4 is not conserved beyond the Saccharomycotina, and ATF4 is not conserved beyond metazoans. In fission yeast Schizosaccharomyces pombe, a GATA-type transcription factor called Fil1, which lacks any sequence homology to GCN4 or ATF4, mediates the amino acid starvation response through similar regulatory mechanisms. This remarkable example of transcriptional network plasticity demonstrates that evolution can maintain conserved regulatory principles while substituting nonorthologous transcription factors.
Beyond its role in starvation responses, GCN4 has been found to reduce protein synthesis capacity and extend yeast lifespan, suggesting that the growth-limiting functions of the GCN4/ATF4 pathway may have beneficial effects on organismal longevity. This is consistent with observations that ATF4 activity is a common feature shared by multiple slow-aging mouse models.
ATF4 is described as "the main effector of the integrated stress response (ISR)" [pakos-zebrucka-2016-isr-review-summary], a fundamental cellular adaptation mechanism that helps cells respond to diverse stressors while maintaining homeostasis. The ISR is activated when any of four stress-sensing kinases phosphorylate eIF2α at serine 51, converging on the common outcome of reduced global translation and increased ATF4 synthesis.
The four eIF2α kinases respond to distinct stress stimuli: PERK (PKR-like endoplasmic reticulum kinase) is activated by accumulation of misfolded proteins in the endoplasmic reticulum; GCN2 (general control nonderepressible 2) responds to amino acid deprivation and uncharged tRNA accumulation; PKR (double-stranded RNA-dependent protein kinase) is activated by viral double-stranded RNA; and HRI (heme-regulated eIF2α kinase) responds to heme deficiency and mitochondrial stress primarily in erythroid cells. Despite these different upstream triggers, all four kinases converge on eIF2α phosphorylation and subsequent ATF4 induction, providing a unified cellular response to diverse stresses.
Once translated, ATF4 accumulates in the nucleus where it binds to specific DNA regulatory elements to activate transcription of stress-responsive genes. ATF4 regulates target genes through C/EBP-ATF response elements (CAREs), which can mediate transcriptional activation in response to various stimuli. The gene expression program activated by the ISR is context-dependent, influenced by the cellular identity, the nature and intensity of the stress, and the duration of stress exposure. While the ISR is primarily a pro-survival, homeostatic program, prolonged or severe stress can redirect ATF4 signaling toward pro-apoptotic outcomes [pakos-zebrucka-2016-isr-review-summary].
ATF4 plays a central role in the PERK arm of the unfolded protein response (UPR), the cellular program activated when misfolded proteins accumulate in the endoplasmic reticulum. Under ER stress conditions, the ER chaperone BiP (immunoglobulin binding protein) dissociates from the luminal domain of PERK, allowing PERK oligomerization and trans-autophosphorylation. Active PERK then phosphorylates eIF2α, leading to both global translation attenuation and preferential ATF4 synthesis.
ATF4 translocates to the nucleus where it induces expression of ER chaperones, autophagy/apoptosis genes, oxidative response genes, and amino acid metabolism pathways. A key target of ATF4 during ER stress is CHOP (C/EBP homologous protein, also known as DDIT3), a transcription factor that can form heterodimers with ATF4 to regulate additional downstream genes. However, studies in liver-specific ATF4 knockout mice revealed that ATF4's role in the UPR is more limited than previously appreciated from cell culture studies [fusakio-2016-atf4-liver-summary]. RNA-Seq analysis indicated that ATF4 affects only approximately 7.5% of stress-regulated genes in liver, compared to nearly 50% for PERK, suggesting that PERK activates multiple transcriptional networks beyond ATF4. Furthermore, in liver exposed to ER stress, CHOP expression occurs independently of ATF4, with ATF6 serving as a major contributor to CHOP induction.
Nevertheless, ATF4 has tissue-specific and context-dependent roles in the UPR. It is essential for expression of genes involved in oxidative stress response both basally and under stress conditions, and for cholesterol metabolism genes. ATF4 deletion in liver results in increased free cholesterol accumulation under stress and altered cholesterol homeostasis [fusakio-2016-atf4-liver-summary].
ATF4 regulates a diverse set of target genes that control cellular adaptation to stress. Neill and Masson catalogued 41 well-validated ATF4 target genes across multiple studies [neill-2023-atf4-review-summary], which can be grouped into several functional categories.
Amino Acid Biosynthesis and Transport: ATF4 is a master regulator of amino acid metabolism, controlling genes essential for biosynthesis of non-essential amino acids and amino acid uptake. Key targets include ASNS (asparagine synthetase), which catalyzes the conversion of aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. During amino acid limitation, ATF4 binding to the amino acid response element (AARE) in the ASNS promoter occurs within 30-60 minutes of amino acid deprivation and continues for 3-4 hours. Other amino acid metabolism targets include PSAT1 (phosphoserine aminotransferase 1) and PHGDH (phosphoglycerate dehydrogenase) involved in serine biosynthesis, as well as amino acid transporters such as SLC7A11 (the cystine/glutamate antiporter xCT) and SLC1A5.
Aminoacyl-tRNA Synthetases: ATF4 induces the expression of 15 aminoacyl-tRNA synthetases, including CARS (cysteinyl-tRNA synthetase), GARS (glycyl-tRNA synthetase), AARS (alanyl-tRNA synthetase), and SARS (seryl-tRNA synthetase). This coordinated upregulation ensures that cells have adequate capacity for protein synthesis when amino acid availability is restored.
Autophagy: ATF4 directly regulates autophagy genes through binding to CRE sites in their promoters. Key autophagy targets include MAP1LC3B (LC3B, a core autophagosome membrane component), BECN1 (Beclin 1), ATG5, ATG7, ATG12, ATG16L1, GABARAP, and the cargo receptors p62/SQSTM1 and NBR1 [rouschop-2010-autophagy-summary]. During severe hypoxia, ATF4 facilitates autophagy through direct binding to the LC3B promoter, providing a mechanistic link between the UPR and the autophagic machinery.
Oxidative Stress Response: ATF4 regulates genes that protect cells from oxidative damage, including CTH (cystathionine gamma-lyase), SOD2 (superoxide dismutase 2), and xCT/SLC7A11. The induction of xCT is particularly important because it imports cystine for glutathione biosynthesis, the major cellular antioxidant system [lewerenz-2012-atf4-oxidative-summary]. Recent studies have revealed that ATF4 is an obligatory metabolic activator of NRF2, increasing NRF2 transcription and inducing the glutathione-degrading enzyme CHAC1, which is critically important for maintaining NRF2 activation.
Pro-apoptotic Factors: Under conditions of prolonged or severe stress, ATF4 can induce pro-apoptotic genes including CHOP/DDIT3, PUMA, NOXA, and TRB3. The ATF4-CHOP axis is particularly important for the cell death decision. CHOP, an ATF4 target gene and heterodimerization partner, can trigger the intrinsic apoptotic pathway through inhibition of BCL-2 and upregulation of BIM, as well as the extrinsic pathway through upregulation of death receptors DR4 and DR5.
ATF4 contains a nuclear localization sequence within its C-terminal region that mediates its transport to the nucleus following synthesis. Under basal conditions, ATF4 shows diffuse cellular distribution in both cytoplasm and nucleus at low levels. Upon activation of the ISR, ATF4 protein accumulates and translocates to the nucleus to activate target gene transcription. Studies on TLR4 signaling have documented the kinetics of this translocation: ATF4 initially moves to the cytoplasmic membrane within 5 minutes of stimulation, then gradually enters the nucleus by 15 minutes, achieving complete nuclear localization by 60 minutes.
In neurons, ATF4/CREB2 localizes to distal dendrites and shows importin-mediated retrograde transport to the soma and nucleus. Biochemical studies have demonstrated that ATF4 binds specifically to importins α1 and α6, and this binding is required for transport from distal dendrites to the nucleus. This dendritic localization may be relevant to ATF4's reported role in modulating synaptic plasticity and long-term memory formation.
Importantly, trafficking of ATF4 to the nucleus does not require additional signals from stress pathways beyond its synthesis; ectopically expressed ATF4 localizes predominantly to the nuclear compartment. The Human Protein Atlas documents ATF4 primarily as a nuclear protein with predominant localization in cardiomyocytes.
ATF4 protein is highly unstable, with a short half-life that allows for rapid changes in protein levels in response to changing conditions. Neill and Masson documented 33 post-translational modifications affecting ATF4, concentrated in the N-terminal and C-terminal bZIP domain regions [neill-2023-atf4-review-summary]. These modifications critically influence ATF4 activity, stability, and target gene selection.
Phosphorylation is the most extensively characterized modification class. Phosphorylation at serine 219 is required for βTRCP-mediated proteasomal degradation, providing a mechanism for rapid ATF4 turnover when stress is resolved. Casein kinase 2 (CK2)-mediated phosphorylation at serine 215, in contrast, increases ATF4 transcriptional activity. RET kinase phosphorylation at multiple sites (T107, T114, T115, T119) reduces expression of pro-apoptotic target genes, potentially biasing ATF4 activity toward pro-survival outcomes. The intricate coupling between the transactivation and bZIP domains governs the efficiency of CK2-mediated phosphorylation, indicating that ATF4's structural organization influences its post-translational regulation.
The balance between ATF4 synthesis and degradation determines net protein levels and, consequently, the transcriptional output. During stress, increased synthesis coupled with stabilization leads to ATF4 accumulation. The ISR includes a negative feedback loop through ATF4-dependent induction of GADD34, which combines with PP1 to dephosphorylate eIF2α and restore normal translation, thereby reducing further ATF4 synthesis.
Studies in ATF4 knockout mice have revealed essential physiological functions for this transcription factor in multiple tissues and developmental processes. ATF4-deficient mice exhibit abnormal lens formation, growth retardation, anemia, and delayed bone development.
Lens Development: Adult homozygous Atf4 null mice invariably exhibit severe microphthalmia (small eyes) arising late in embryonic development due to complete aphakia (absence of the eye lens). This phenotype results from p53-mediated apoptosis of anterior lens epithelial cells. RNA-seq analysis revealed that E16.5 Atf4 null mouse lenses show downregulation of lens epithelial markers and markers of late lens fiber cell differentiation. ATF4 appears to function by metabolically adapting the avascular lens to its unique environment.
Bone Development and Homeostasis: ATF4 is critical for bone formation and homeostasis. A landmark 2004 study by Yang, Karsenty, and colleagues identified ATF4 as an essential regulator of osteoblast biology and demonstrated that ATF4 is a critical substrate of the kinase RSK2 [yang-2004-atf4-rsk2-bone-summary]. ATF4-deficient mice display dramatically reduced bone mass and bone formation rate, with severe osteopenia, impaired osteoblast terminal differentiation, reduced osteocalcin expression, and decreased Type I collagen synthesis. The mice show delayed skeletal development and thereafter develop a severe low-bone-mass phenotype caused by decreased bone formation. At the molecular level, ATF4 activates osteocalcin transcription through the osteocalcin-specific element 1 (OSE1) in the promoter and promotes osteoblast differentiation. RSK2 phosphorylates ATF4 at serine 251 (mouse) or serine 245 (human), and this phosphorylation is required for ATF4 to regulate collagen synthesis and osteocalcin expression in osteoblasts. Importantly, the shared skeletal phenotypes between Atf4-deficient and Rsk2-deficient mice suggest that lack of ATF4 phosphorylation by RSK2 contributes to the skeletal abnormalities observed in Coffin-Lowry Syndrome, a human genetic disorder caused by RSK2 mutations. ATF4 also promotes bone angiogenesis by increasing VEGF expression and release in the bone environment, and ablation of Atf4 severely impairs skeletal vasculature with reduced microvascular density and decreased expression of HIF-1α and VEGF in osteoblasts. Notably, the connection between ATF4's role in amino acid import and bone formation has nutritional implications: a high-protein diet can partially rescue the skeletal defects in Atf4-deficient mice, highlighting how ATF4 links bone formation to nutritional status.
Metabolism and Energy Homeostasis: ATF4-null mice are lean, mildly hypoglycemic, and resistant to obesity induced by aging or high-energy diets. This metabolic phenotype suggests roles for ATF4 in lipid metabolism and energy expenditure. Interestingly, ATF4 activity has been identified as a common feature shared by many kinds of slow-aging mice.
Hematopoiesis: ATF4-deficient mice show defects in production of erythrocytes by the fetal liver, consistent with the sensitivity of erythroid cells to stress via the HRI kinase pathway.
ATF4, originally identified as CREB-2, has emerged as an important regulator of synaptic plasticity and memory formation, although its precise role remains complex and context-dependent [chen-2003-atf4-memory-summary]. The initial characterization of ATF4's role in memory came from studies in the marine mollusk Aplysia, where the ATF4 homolog ApCREB-2 was identified as an inhibitor of CREB-dependent long-term facilitation (LTF). This finding established the model that ATF4 functions as a "memory suppressor" gene, constraining the formation of long-term memories by opposing CREB-mediated transcription.
In the mammalian hippocampus, the molecular basis of long-term memory involves gene expression mediated by the transcription factor CREB. ATF4 can heterodimerize with CREB and other bZIP factors to repress transcription from CRE-containing promoters, thereby restraining the gene expression programs required for memory consolidation. In 2003, Chen and colleagues demonstrated that transgenic mice expressing a dominant-negative inhibitor of ATF4 and C/EBP proteins (EGFP-AZIP) exhibited enhanced hippocampal-based spatial memory and enhanced long-term potentiation (LTP), a cellular correlate of memory. More recent studies using conditional knockout approaches confirmed that deletion of ATF4 specifically in forebrain excitatory neurons lowers the threshold for LTP induction and enhances long-term memory formation.
The subcellular localization of ATF4 in neurons is particularly relevant to its function in plasticity. ATF4/CREB2 localizes to distal dendrites of hippocampal neurons, where it binds to specific importin α isoforms (importin α1 and α6) for retrograde transport to the nucleus. This dendritic localization positions ATF4 to respond to local synaptic signals and translate them into nuclear transcriptional responses. During long-term synaptic plasticity, ATF4 is removed through ubiquitin-proteasome-mediated proteolysis, relieving its inhibition of CREB-dependent gene expression.
However, the role of ATF4 in memory is not simply inhibitory. Emerging evidence suggests that ATF4 may also have positive functions in specific memory processes, including consolidation of object recognition memory, formation of fear extinction memory, and memory flexibility. A recent study demonstrated that elevating ApCREB2 (the Aplysia ATF4 homolog) post-synaptically increased synaptic strength, while doing so pre-synaptically decreased synaptic strength, indicating that ATF4's effects on plasticity are cell-type and compartment-specific. These findings suggest that ATF4 functions as a regulator of excitability and plasticity thresholds rather than a simple memory suppressor, with its net effect depending on cellular context, timing, and the specific memory process involved.
A central question in ATF4 biology is how cells decide between adaptive survival and apoptotic death outcomes during stress. The ISR can output two contradicting outcomes, and ATF4 "pulls multiple potential levers" that can lead to either outcome [neill-2023-atf4-review-summary]. Evidence suggests that the choice depends on multiple factors including heterodimerization partner availability, post-translational modification patterns, stress duration and intensity, and cell type-specific properties.
The relative abundance of different heterodimerization partners appears crucial. CEBPG is the main ATF4 partner for inducing pro-survival stress-responsive genes. In contrast, ATF4-CHOP heterodimers preferentially activate genes that promote apoptosis. The temporal dynamics of ATF4 signaling also matter: early and transient ATF4 activation typically promotes adaptation, while sustained ATF4/CHOP activation shifts the balance toward cell death.
CHOP-mediated apoptosis occurs through multiple mechanisms. CHOP triggers the intrinsic apoptotic pathway through inhibition of BCL-2 and upregulation of BIM and PUMA, which promote BAX-BAK-mediated mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation. CHOP also directly induces death receptor 5 (DR5) expression, activating the extrinsic apoptotic pathway through FADD and caspase-8. Additionally, CHOP activates calcium-mediated apoptosis through ERO1α, which promotes ER calcium release and downstream CaMKII signaling.
Terminally differentiated cells such as neurons may suppress apoptotic pathways to favor survival, reflecting cell type-specific regulation of the ATF4 response network.
Given ATF4's central role in stress responses and cell fate decisions, it has emerged as a potential therapeutic target for multiple disease contexts.
Cancer: Many cancer cells exploit the ISR-ATF4 pathway to survive nutrient-poor, hypoxic tumor microenvironments. ATF4-dependent induction of amino acid biosynthesis and transport genes supports tumor cell proliferation under metabolic stress. Elevated ASNS expression, an ATF4 target, is associated with resistance to asparaginase therapy in acute lymphoblastic leukemia and may predict drug sensitivity in solid tumors. Targeting the PERK-ATF4-CHOP pathway has been explored as a strategy to induce cancer cell death, with compounds that activate this pathway showing efficacy against HTLV-1-infected cells.
Neurodegeneration: The ISR has been implicated in neurodegenerative diseases where protein misfolding and ER stress occur. ISR enhancers such as Guanabenz and Sephin1, which inhibit GADD34 and prolong eIF2α phosphorylation, show potential benefits in some neurodegenerative contexts. Conversely, ISRIB (integrated stress response inhibitor), which renders cells insensitive to eIF2α phosphorylation, has shown cognitive-enhancing effects in aged mice.
Metabolic Disease: ATF4's roles in lipid metabolism, glucose homeostasis, and energy expenditure suggest potential relevance to obesity and diabetes therapies.
Despite extensive research on ATF4, several important questions remain unresolved:
Heterodimerization Specificity: What determines which dimerization partner ATF4 associates with in a given cellular context, and how does this selection mechanism operate at the molecular level?
Cell Fate Decision Mechanism: What is the precise mechanism that determines whether ATF4 activation leads to adaptive survival or apoptosis? How do cells "integrate" stress intensity and duration into this decision?
Tissue-Specific Functions: How do ATF4's functions differ across tissues, and what accounts for the tissue-specific phenotypes in ATF4 knockout mice? Are there tissue-specific dimerization partners or post-translational modifications?
ATF4 in Immunity: Emerging evidence suggests roles for ATF4 in immune cell function and inflammation. What are the specific functions of ATF4 in different immune cell populations?
Non-transcriptional Functions: Does ATF4 have functions beyond transcriptional regulation, such as cytoplasmic roles or direct protein-protein interactions that influence signaling?
Therapeutic Window: For therapeutic modulation of the ATF4 pathway, what is the optimal approach to achieve beneficial effects while avoiding adverse outcomes in normal tissues?
Evolution of ATF4 Regulation: The uORF-mediated translational control mechanism is highly conserved from yeast (GCN4) to mammals. What evolutionary pressures maintained this complex regulatory mechanism, and are there species-specific variations in ATF4 function?
[neill-2023-atf4-review-summary] Neill G, Masson GR. A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response. Front Mol Neurosci. 2023;16:1112253. PMID: 36825279; PMCID: PMC9941348. doi:10.3389/fnmol.2023.1112253. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC9941348/
[pakos-zebrucka-2016-isr-review-summary] Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374-1395. PMID: 27629041; PMCID: PMC5048378. doi:10.15252/embr.201642195. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5048378/
[karpinski-1992-creb2-cloning-summary] Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM. Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proc Natl Acad Sci U S A. 1992;89(11):4820-4824. PMID: 1534408; PMCID: PMC49179. doi:10.1073/pnas.89.11.4820. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC49179/
[young-wek-2016-uorf-summary] Young SK, Wek RC. Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response. J Biol Chem. 2016;291(33):16927-16935. PMID: 27358398; PMCID: PMC5016099. doi:10.1074/jbc.R116.733899. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5016099/
[fusakio-2016-atf4-liver-summary] Fusakio ME, Willy JA, Wang Y, Mirek ET, Al Baghdadi RJ, Adams CM, Anthony TG, Wek RC. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol Biol Cell. 2016;27(9):1536-1551. PMID: 26960794; PMCID: PMC4850040. doi:10.1091/mbc.E16-01-0039. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC4850040/
[rouschop-2010-autophagy-summary] Rouschop KM, van den Beucken T, Dubois L, et al. Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene. 2010;29(31):4424-4435. PMID: 20514020. doi:10.1038/onc.2010.191. URL: https://pubmed.ncbi.nlm.nih.gov/20514020/
[lewerenz-2012-atf4-oxidative-summary] Lewerenz J, Maher P. Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression. Cell Death Differ. 2011;18(5):847-858. PMID: 21200489. doi:10.1038/cdd.2011.165. URL: https://pubmed.ncbi.nlm.nih.gov/21200489/
C/EBPβ-ATF4 structure: Podust LM, Krezel AM, Kim Y. Crystal structure of the CCAAT box/enhancer binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA. J Biol Chem. 2001;276(1):505-513. PMID: 11018027. doi:10.1074/jbc.M005594200. URL: https://pubmed.ncbi.nlm.nih.gov/11018027/
ATF4-NRF2 interaction: Sarcinelli C, Sharma H, Mossoba ME, et al. The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2. Cell Rep. 2023;42(7):112724. PMID: 37410595. doi:10.1016/j.celrep.2023.112724. URL: https://pubmed.ncbi.nlm.nih.gov/37410595/
ASNS regulation: Kilberg MS, Balasubramanian M, Fu L, Shan J. The transcription factor network associated with the amino acid response in mammalian cells. Adv Nutr. 2012;3(3):295-306. PMID: 22585903; PMCID: PMC3649461. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC3625782/
PERK-ATF4-CHOP pathway: Wang M, Kaufman RJ. The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress. Curr Mol Med. 2016;16(6):533-544. PMID: 27211800; PMCID: PMC5008685. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5008685/
CHOP review: Yang Y, Liu L, Naik I, Braunstein Z, Zhong J, Ren B. Transcription Factor C/EBP Homologous Protein in Health and Diseases. Front Immunol. 2017;8:1612. PMID: 29230208; PMCID: PMC5711810. doi:10.3389/fimmu.2017.01612. URL: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01612/full
ATF4 B2 motif: Shirafuji T, et al. Fine-Tuning of ATF4 DNA Binding Activity by a Secondary Basic Motif Unique to the ATF-X Subfamily of bZip Transcription Factors. Biochemistry. 2024. doi:10.1021/acs.biochem.4c00640. URL: https://pubs.acs.org/doi/10.1021/acs.biochem.4c00640
Importin-mediated transport: Lai KO, Zhao Y, Ch'ng TH, Martin KC. Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons. Proc Natl Acad Sci U S A. 2008;105(44):17175-17180. PMID: 18957548; PMCID: PMC2579388. doi:10.1073/pnas.0803906105. URL: https://www.pnas.org/doi/10.1073/pnas.0803906105
Human Protein Atlas - ATF4: Subcellular localization. URL: https://www.proteinatlas.org/ENSG00000128272-ATF4/subcellular
[yang-2004-atf4-rsk2-bone-summary] Yang X, Matsuda K, Bialek P, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: implication for Coffin-Lowry Syndrome. Cell. 2004;117(3):387-398. PMID: 15109498. doi:10.1016/S0092-8674(04)00344-7. URL: https://pubmed.ncbi.nlm.nih.gov/15109498/
[hinnebusch-2005-gcn4-review-summary] Hinnebusch AG. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol. 2005;59:407-450. PMID: 16153175. doi:10.1146/annurev.micro.59.031805.133833. URL: https://pubmed.ncbi.nlm.nih.gov/16153175/
[chen-2003-atf4-memory-summary] Chen A, Muzzio IA, Bhardwaj SK, et al. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron. 2003;39(4):655-669. PMID: 12925279. doi:10.1016/S0896-6273(03)00501-4. URL: https://pubmed.ncbi.nlm.nih.gov/12925279/
ATF4 in fission yeast: Duncan CDS, Rodriguez-Lopez M, Rechnitzer C, et al. General amino acid control in fission yeast is regulated by a nonconserved transcription factor, with functions analogous to Gcn4/Atf4. Proc Natl Acad Sci U S A. 2018;115(8):E1829-E1838. PMID: 29432178; PMCID: PMC5828588. doi:10.1073/pnas.1713991115. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5828588/
GCN4 and lifespan: Postnikoff SDL, Johnson JE, Tyler JK. The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan. Nat Commun. 2017;8:457. doi:10.1038/s41467-017-00539-y. URL: https://www.nature.com/articles/s41467-017-00539-y
ATF4 deletion enhances LTP: Oren DA, Bhardwaj SK, et al. The ISR downstream target ATF4 represses long-term memory in a cell type–specific manner. Proc Natl Acad Sci U S A. 2024. PMID: pending. doi:10.1073/pnas.2407472121. URL: https://www.pnas.org/doi/10.1073/pnas.2407472121
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BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATF4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene ATF4 (gene ID: ATF4, UniProt: P18848) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATF4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene ATF4 (gene ID: ATF4, UniProt: P18848) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Research plan and verification
- Identity check: The protein of interest is human ATF4 (UniProt P18848), a basic leucine zipper (bZIP) transcription factor historically known as CREB-2/CREB2. It belongs to the bZIP family (IPR004827; PF00170) and functions predominantly as a nuclear DNA-binding factor. This aligns with the integrated stress response (ISR) effector ATF4 extensively described in the human literature.
- Organism: Homo sapiens (Human) is correct.
- Family/domains: bZIP DNA-binding and dimerization domain, consistent with ATF4’s requirement to homo- or heterodimerize with other bZIP factors (e.g., C/EBP family, CHOP/DDIT3, ATF3) to regulate transcription.
Executive summary
ATF4 is the principal transcriptional effector of the ISR that is preferentially translated when eIF2α is phosphorylated by the stress-sensing kinases PERK, GCN2, HRI, or PKR. In the nucleus, ATF4 dimerizes via its bZIP domain and binds C/EBP–ATF response elements (CARE/AARE) to control genes in amino-acid transport and biosynthesis (e.g., ASNS, SLC7A11/Slc7a11), redox balance (SESN2, ATF5, CHAC1), autophagy/mitophagy (BNIP3), proteostasis (DDIT3/CHOP), and metabolic rewiring (REDD1/DPHL4, SESN2), thereby determining adaptive survival or, under chronic stress, pro-death outcomes. Beyond canonical translation control by uORFs in the ATF4 5′UTR, emerging work in 2023–2024 refined ISR–translation coupling (eIF2B allostery; GCN2 paradoxical activation by kinase inhibitors), ATF4’s chromatin engagement and crosstalk with mTORC1 and STING, and disease-directed applications (cardiotoxicity mitigation, oncology metabolism, neurodegeneration trials of ISR modulators).
1) Key concepts and definitions with current understanding
- Molecular identity and domain architecture: ATF4 is a bZIP transcription factor (PF00170) that dimerizes and binds CARE/AARE motifs to activate or repress transcription. It is cytosol-synthesized and primarily nuclear-localized upon stress, with regulated nuclear import/export mediated by importin pathways and interaction partners.
- Core pathway: Integrated stress response (ISR)
• Four eIF2α kinases sense distinct stresses: PERK (ER proteostasis), GCN2 (amino acid/translation stress), HRI (heme/mitochondrial stress, OMA1–DELE1–HRI axis), PKR (viral dsRNA). Phosphorylated eIF2α lowers ternary complex (TC) and global initiation, but increases translation of uORF-programmed mRNAs including ATF4.
• ATF4 target program: amino-acid transporters and biosynthetic enzymes (e.g., ASNS), redox defense (SLC7A11, SESN2), autophagy/mitophagy and mitochondrial homeostasis (BNIP3), apoptosis switch with CHOP (DDIT3), and feedback (GADD34/PPP1R15A) that dephosphorylates eIF2α.
• Cross-pathway crosstalk: ATF4 interface with mTORC1 (REDD1, SESN2), cGAS–STING–PERK–eIF2α, and lysosome-v-ATPase–mTORC1 signaling that can directly phosphorylate ATF4 (UPRmt context).
- Translation control of ATF4: Two upstream ORFs (uORFs) in the 5′UTR enforce low basal ATF4 translation; p-eIF2α reduces re-initiation at inhibitory uORFs, enabling main ORF translation. Additional modifiers include termination efficiency, eIF3 subunit stoichiometry, and noncanonical initiation factors; the role of eIF2A appears minor in many human contexts.
- Dimerization partners: ATF4 forms homo- or heterodimers (e.g., CHOP/DDIT3, C/EBP family, ATF3), and partner choice, post-translational modifications, and chromatin context help determine adaptive versus apoptotic outputs.
2) Recent developments and latest research (2023–2024 priority)
- Allostery at the ISR hub (eIF2B) and pharmacology: Structural and biochemical work in 2023–2024 delineated a central helical fulcrum/switch-helix in eIF2B controlling active/inactive states and the ISRIB pocket mechanism, sharpening how ISRIB-like activators restore eIF2B function and limit ATF4 induction in disease models.
- Paradoxical activation of GCN2 by ATP-competitive kinase inhibitors: Multiple 2024 studies show RAF/BRAF and even nominal GCN2 inhibitors can allosterically activate GCN2, inducing eIF2α-P and ATF4; this off-target ISR activation modulates therapeutic responses, highlighting assay and design needs for true GCN2 inhibitors.
- Mitochondrial ISR signaling refinement: OMA1–DELE1–HRI axis and lysosome–v-ATPase–mTORC1-dependent ATF4 phosphorylation integrate mitochondrial and lysosomal signals, separating UPRmt from UPRER outputs and positioning ATF4 as a convergence node for organelle stress.
- ISR-selective activation reveals metabolic rewiring: Synthetic selective ISR activation shows an ATF4-centered module rerouting carbon toward amino-acid production and away from TCA/lipogenesis, with an ATF4-independent lipid droplet program—refining our map of ISR sufficiency and partitioning of outputs.
- Chromatin and occupancy logic: ATF4’s stress-selective transcription appears conditioned by pre-established occupancy and chromatin organization with partner bZIPs; this supports cell type– and stimulus-specific gene programs.
- Disease-focused advances
• Cardiotoxicity: GCN2–ATF4 drives ponatinib cardiotoxicity; ISRIB mitigates in cell and mouse models without impairing anti-tumor actions, motivating ISR modulators for safety management.
• Oncology: ISR–ATF4 supports metabolic plasticity (glutamine axis, uORF-driven oncogene translation such as MET under ISR), ferroptosis control via CHAC1/ATF4, and immunomodulation; context-dependent tumor roles reported (e.g., ccRCC ATF4–NUPR1 axis; colon cancer data indicating both pro- and anti-tumor facets depending on context and GCN2 coupling).
• Neuroscience: ATF4 represses long-term memory in excitatory neurons; ISR modulators (ISRIB analogs; eIF2B activators) are under investigation for neurodegeneration and ALS, though translational outcomes are mixed.
• Immunity/virology: Viruses co-opt or suppress ISR; ATF4 mediates antiviral and sometimes proviral programs. ZIKV restriction involves ISR→ATF4→ATF3 innate immune enhancement; EBV LMP1 can inhibit PERK/GCN2 activity, lowering ATF4/CHOP to modulate epithelial differentiation and reactivation.
3) Current applications and real-world implementations
- Small-molecule ISR modulators
• eIF2B activators (ISRIB and clinical analogs) to dampen ISR/ATF4: preclinical neurodegeneration, ALS, mood disorders, and cardiotoxicity mitigation use-cases.
• PERK and GCN2 modulators: tool compounds and early clinical exploration; off-target GCN2 activation by many kinase inhibitors is increasingly recognized and may be leveraged or avoided depending on disease context.
• Emerging strategies: Stabilizers of inhibitory eIF2B–eIF2(αP) complexes (ISR activators) and eIF2B allosteric inhibitors (to upregulate ATF4) in oncology; direct promoter G-quadruplex stabilization of ATF4 to suppress tumor persisters in glutamine restriction.
- Therapeutic areas
• Oncology: Targeting ISR nodes to sensitize tumors (e.g., WEE1 inhibitor synergy with ISR activation; leveraging GCN2–ATF4 to overcome metabolic vulnerabilities; combining ISR modulators with immunotherapy or ribosome biogenesis inhibitors). Caution: cell-type and context determine whether ATF4 promotes survival or apoptosis.
• Cardio-oncology: ISR damping (eIF2B activation) counters TKI-induced mitochondrial stress and ATF4 hyperactivation.
• Neurology: eIF2B activators to normalize translation and reduce maladaptive ATF4 programs; cell-type–specific ATF4 ablation improves memory in mice, encouraging selective targeting.
• Bone biology/regeneration: PERK–eIF2α–ATF4 axis supports osteoblast lineage differentiation and skeletal anabolism; ATF4 regulates osteogenic targets (e.g., BNIP3-mediated mitophagy, PSAT1, and β-catenin coupling) and systemic metabolism via osteoblasts.
4) Expert opinions and analysis
- ATF4 as a tunable switch: Partner selection (e.g., CHOP vs. C/EBP), PTMs, and chromatin priming bias ATF4 toward adaptive or apoptotic outputs. Short, pulsatile ISR favors adaptive amino-acid/redox gene programs; chronic, high-amplitude ISR favors CHOP, GADD34 and apoptotic genes.
- Precision ISR pharmacology: Recent structural and chemical biology clarify why ISRIB-class eIF2B activators work and why ATP-competitive kinase inhibitors paradoxically activate GCN2. This underlines a precision approach: choose ISR levers (eIF2B, kinases, phosphatases) and timing (acute vs. chronic) to achieve desired ATF4 output.
- Disease-context heterogeneity: ATF4’s role is tissue- and state-specific—pro-survival in nutrient stress, pro-death in persistent ER stress. In cancer, ATF4 can enable metabolic adaptation and drug tolerance, yet excessive ISR can be exploited for synthetic lethality.
5) Relevant statistics and recent data highlights
- Cardiotoxicity model: In human iPSC cardiomyocytes and mouse models exposed to ponatinib, GCN2-mediated ISR activation increased ATF4 and CHOP; ISRIB treatment improved cardiac function readouts and protected cells without blunting anti-tumor activity (preclinical quantitative proteomics and functional assays).
- Selective ISR activation profiling: Time-/dose-resolved multi-omics indicate a compact, sensitive ATF4 transcriptional module predominantly encompassing amino-acid metabolism genes, with measurable bioenergetic rerouting away from TCA/fatty acid synthesis and quantifiable lipid droplet biogenesis via DGAT enzymes (ATF4-independent arm).
- eIF3 remodeling and ATF4 translation: Ribo-seq in HeLa cells upon eIF3 subunit manipulations shows ATF4 uORF-program sensitivity, quantitatively altering ATF4 translation alongside other short-uORF mRNAs.
- Clinical-translational: ISR modulators (e.g., eIF2B activators) are in or have completed early-phase trials in ALS and other indications; multiple kinase inhibitors show measurable ISR/ATF4 activation signatures in cells, explaining efficacy/toxicity dimensions.
Functional annotation: mechanism, substrates/targets, localization, pathways
- Primary function: sequence-specific transcription factor. Not an enzyme, transporter, or structural cytoskeleton component. It binds DNA as a bZIP dimer to regulate transcription of stress-response genes.
- DNA recognition/partnering: Binds CARE/AARE elements; partner choice (CHOP, ATF3, C/EBPβ, others) modulates activation vs repression and gene set selection.
- Subcellular localization: Synthesized on cytosolic ribosomes; accumulates in the nucleus upon stress. Nuclear import is facilitated by importins (e.g., KPNB1), and ATF4 shuttling has been reported in specific contexts with regulated nuclear retention.
- Pathways/context of action
• ISR: PERK/GCN2/HRI/PKR → eIF2α-P → increased ATF4 translation → transcriptional program (ASNS, SLC7A11, SESN2, GADD34, DDIT3/CHOP, TRIB3, REDD1, ATF5, CHAC1). Feedback: GADD34 dephosphorylates eIF2α.
• Mitochondrial stress/UPRmt: OMA1–DELE1–HRI axis; lysosome–v-ATPase–mTORC1 phosphorylates ATF4 to promote UPRmt; ATF4 targets support mitochondrial redox and proteostasis.
• mTORC1 crosstalk: ATF4 targets (REDD1, SESN2) suppress mTORC1; prolonged ATF4 can drive chronic mTOR suppression linked to neurodegeneration models.
• Immunity/viral stress: ATF4 mediates antiviral and inflammatory programs, intersects with ATF3/CHOP; viruses may suppress or hijack ATF4 signaling.
• Bone and connective tissue: ATF4 required for osteoblast differentiation and matrix gene expression; integrates with β-catenin/Runx2; regulates BNIP3-dependent mitophagy.
Selected 2023–2024 references and resources (titles with publication year; include representative URLs)
- Nature Chemical Biology (2024): A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling. https://doi.org/10.1038/s41589-023-01453-9
- eLife (2024): Perturbations in eIF3 subunit stoichiometry alter expression of… including ATF4 uORF sensitivity. https://doi.org/10.7554/eLife.95846
- Cell Discovery (2023): Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation. https://doi.org/10.1038/s41421-023-00589-1
- Nature Communications (2024): Specific activation of the ISR uncovers regulation of central carbon metabolism and lipid droplet biogenesis. https://doi.org/10.1038/s41467-024-52538-5
- Circulation Research (2024): Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity (ISRIB protective). https://doi.org/10.1161/CIRCRESAHA.123.323683
- Frontiers in Cell Dev Biol (2024): Activating transcription factor 4: a regulator of stress response in human cancers. https://doi.org/10.3389/fcell.2024.1370012
- NAR Cancer (2024): Upstream open reading frames: new players… (ATF4 paradigm). https://doi.org/10.1093/narcan/zcae023
- Acta Pharmacol Sin (2024): Mammalian integrated stress responses in stressed organelles and their functions. https://doi.org/10.1038/s41401-023-01225-0
- Biology (2024): ATF4 Signaling in HIV-1 Infection. https://doi.org/10.3390/biology13030146
- J Biol Chem (2024): LC3A-mediated autophagy elicits PERK–eIF2α–ATF4 axis activation… https://doi.org/10.1016/j.jbc.2024.107398
- Cell Reports Medicine (2024): Ex vivo activation of the GCN2 pathway reprograms T cells for ACT. https://doi.org/10.1016/j.xcrm.2024.101465
- EMBO J (2025 online Jan; mechanism relevant in 2024): ISR drives MET oncogene overexpression via uORFs. https://doi.org/10.1038/s44318-024-00338-4
- PNAS (2024): ATF4 represses long-term memory in a cell type–specific manner. https://doi.org/10.1073/pnas.2407472121
Open questions and best practices for functional studies
- Dissect partner-specific outputs: Use motif-centric ChIP-seq/CUT&RUN with perturbation of CHOP, C/EBPβ, ATF3 to parse survival vs apoptosis programs.
- Temporal ISR control: Time-resolved phospho-proteomics and nascent RNA-seq to separate early adaptive ATF4 targets from late CHOP-dominant programs.
- Translation-level quantification: Reporter constructs with WT/mutated ATF4 uORFs; Ribo-seq under graded eIF2B activation to map ATF4 translation thresholds.
- Subcellular dynamics: Live-cell imaging of ATF4 nuclear import/export (e.g., KPNB1 dependence) under distinct kinase activation (PERK vs GCN2 vs HRI).
Limitations of current evidence
- Context dependence: Many results are cell-type– or stressor-specific; extrapolation requires care.
- Off-target pharmacology: Several kinase inhibitors engage ISR nodes unintentionally, complicating attribution unless orthogonal validation is performed.
Conclusion
Human ATF4 (UniProt P18848) is a bZIP transcription factor at the core of the ISR, integrating diverse organelle and environmental stresses through translation reprogramming to execute targeted transcriptional programs. Recent 2023–2024 advances sharpen mechanistic understanding at the ISR hub (eIF2B allostery), reveal unanticipated drug–GCN2 interactions, define metabolic rewiring attributable to selective ISR/ATF4 activation, and illuminate translational opportunities in oncology, cardiology, neurology, and bone biology. Future applications will benefit from precise, time- and context-tuned ISR modulation to bias ATF4’s output toward desired adaptive or cytotoxic outcomes.
Note on citations
Because of constraints of this interface, the inline citation IDs requested for each sentence cannot be embedded. To facilitate verification, representative recent sources with URLs and publication dates are listed above for each topic area. If desired, I can expand each claim with a one-to-one mapping to specific 2023–2024 primary papers and add DOIs/links next to each claim.
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BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATF4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene ATF4 (gene ID: ATF4, UniProt: P18848) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Let me plan my response to this comprehensive research query about ATF4 (P18848).
Verification of Gene/Protein Identity: I need to verify that ATF4 (P18848) is indeed a human transcription factor belonging to the bZIP family. From the search results, I can see extensive evidence confirming this is the correct protein.
Major Themes to Cover:
Applications and disease relevance
Organization:
Conclusion
Sources Assessment: The search results provide excellent coverage with recent reviews, primary literature, and structural/biochemical studies. I have sources from 2023-2024 as well as foundational earlier work.
Let me write a comprehensive 10,000+ word report now.
Activating Transcription Factor 4 (ATF4), encoded by the ATF4 gene on human chromosome 22, is a fundamental transcription factor that functions as the central executor of the integrated stress response (ISR)[1][2][7]. Known by several alternative names including cyclic AMP-responsive element-binding protein 2 (CREB-2), tax-responsive enhancer element-binding protein 67 (TaxREB67), and originally identified as a cAMP response element binding protein, ATF4 represents one of the most sophisticated examples of translational and transcriptional gene regulation in mammalian cells[2][4][21]. As a member of the basic region-leucine zipper (bZIP) family of transcription factors, ATF4 binds to cAMP response element (CRE) consensus sequences in the promoters and enhancers of target genes[2][4]. This comprehensive research report examines the molecular mechanisms, regulatory pathways, biological functions, and disease relevance of ATF4, synthesizing evidence from structural biology, biochemistry, cell biology, and clinical studies to elucidate how this single transcription factor orchestrates adaptive responses to diverse cellular stresses while simultaneously maintaining normal metabolic and developmental processes. The dual functionality of ATF4—serving as both a basal metabolic regulator during normal conditions and a master stress-response transcription factor during stress—exemplifies the elegant biological solutions that cells have evolved to maintain homeostasis in the face of environmental challenges.
ATF4 exhibits a characteristic modular architecture composed of distinct functional domains that enable its sophisticated regulation and target gene selectivity[3][29]. The protein consists of an extended N-terminal intrinsically disordered transactivation domain (TAD) spanning approximately residues 1-275, and a C-terminal conditionally ordered basic-leucine zipper (bZip) domain encompassing the DNA-binding basic region and the dimerization leucine zipper motif[3][29][60]. The bZip domain belongs to the broader bZIP superfamily of transcription factors, characterized by a stretch of basic amino acids that form direct contacts with DNA, positioned immediately adjacent to a region of heptad repeats creating a leucine zipper motif critical for protein-protein interactions[2][4]. The consensus DNA binding site recognized by ATF4 is the cAMP response element (CRE), with the canonical sequence 5'-GTGACGT[AC][AG]-3'[2][21], though ATF4 displays flexibility in recognizing asymmetric and palindromic CRE variants depending on its dimerization status and binding context[2][6].
Recent structural and biophysical studies have revealed that the secondary basic motif at the C-terminus of ATF4 (designated B2), which is conserved exclusively with its paralogue ATF5, plays a critical role in mediating interdomain coupling between the transactivation and bZip domains[3]. Through solution NMR spectroscopy and fluorescence polarization assays, researchers demonstrated that this B2 motif serves as the primary driver of transient long-range interactions between the TAD and bZip domains[3]. These intramolecular interactions fundamentally modulate DNA-binding activity and specificity—the presence of the TAD negatively impacts the bZip domain's ability to bind DNA nonspecifically, while paradoxically enhancing specificity for cognate CRE sequences[3]. Importantly, the isolated bZip domain exhibits equal affinity for both CRE and non-CRE DNA sequences, but the full-length ATF4 protein shows dramatically reduced binding to non-cognate sequences, indicating that the disordered TAD functions as a specificity filter[3]. Deletion of the C-terminal B2 motif abolishes this nonspecific binding suppression, highlighting how this conserved structural element precisely tunes DNA-binding selectivity[3].
ATF4 binds DNA through distinct mechanisms dependent on its dimerization status and binding partner identity[2][6]. When functioning as a homodimer, ATF4 recognizes palindromic CRE sequences, each monomer occupying one half of the palindromic site[2]. In contrast, ATF4 forms heterodimers with numerous bZIP proteins from families including C/EBP proteins, other ATF family members (ATF3, ATF5, ATF6), and AP-1 proteins (c-Jun, c-Fos, Fra1)[2][6][57]. These heterodimers bind asymmetric CRE sequences, with the DNA-binding specificity determined by the particular combination of bZIP partners[2][6]. Research using 270 different bZIP transcription factor pairs demonstrated that approximately 72% of bZIP heterodimer pairs bind sequences termed "conjoined half-sites," where the composite binding site consists of the characteristic half-site sequence from each monomer positioned in direct succession[57]. For ATF4-containing heterodimers, this means that the specific target genes regulated depend critically on which bZIP partner ATF4 has dimerized with, providing an elegant molecular mechanism for generating transcriptional specificity from a common upstream stress signal[2][6][57].
The bZIP domains of individual transcription factors within this family contain sufficient information to direct selective heterodimerization through an interhelical salt bridge rule, whereby positively charged residues (primarily lysine and arginine) on one helix interact with negatively charged residues (aspartate and glutamate) on the partner helix[33]. This electrostatic complementarity provides the specificity underlying bZIP heterodimerization, explaining why ATF4 preferentially forms certain heterodimeric combinations while excluding others[33]. ATF4 has been identified as preferentially dimerizing with members of the C/EBP family such as C/EBPβ, C/EBPγ, and C/EBPδ, as well as forming heterodimers with ATF3, JDP2, and other transcription factors[57]. Notably, the specific heterodimeric combination formed appears to be partially dependent on cellular context, stress type, and the relative abundance of potential dimerization partners within the nuclear compartment.
ATF4 functions as the premier molecular effector of the integrated stress response (ISR), a conserved adaptive pathway activated when cells encounter diverse stress signals including endoplasmic reticulum (ER) stress, amino acid deprivation, mitochondrial dysfunction, oxidative stress, heme deficiency, and viral infection[7][10][11][21][28][40]. The ISR operates through a remarkably elegant molecular mechanism centered on the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) at serine 51, catalyzed by one of four stress-responsive serine/threonine kinases: general control nonderepressible 2 (GCN2), protein kinase R-like endoplasmic reticulum kinase (PERK), protein kinase R (PKR), and heme-regulated inhibitor (HRI)[7][10][11][28][52]. Each kinase is activated by distinct stress stimuli with exquisite specificity—GCN2 responds to uncharged (deacylated) transfer RNA accumulation during amino acid starvation[7][8][11], PERK senses accumulation of misfolded proteins in the endoplasmic reticulum[7][11], PKR is activated by double-stranded RNA during viral infection[11], and HRI responds to heme deficiency[11][52].
When eIF2α is phosphorylated at serine 51 by any of these kinases, it forms a stable complex with the guanine nucleotide exchange factor eIF2B[7][28]. This interaction prevents eIF2B-mediated GDP-GTP exchange, thereby blocking the regeneration of active eIF2-GTP ternary complexes required for translation initiation[7]. The consequence is a rapid and dramatic reduction in global protein synthesis as ribosomes lack the activated eIF2-GTP-Met-tRNA complex necessary for scanning initiation codon recognition[7][10]. Remarkably, this global translational shutdown is coupled with a selective activation of ATF4 translation through a translational re-initiation mechanism involving upstream open reading frames (uORFs) in the ATF4 mRNA 5' untranslated region[4][7][10][27][30].
The ATF4 mRNA possesses an exceptionally sophisticated translational control mechanism involving two upstream open reading frames (uORF1 and uORF2) located in its 5' untranslated region[4][10][27][30]. Under unstressed conditions when eIF2-GTP ternary complexes are abundant, ribosomes scanning the 5' UTR efficiently recognize and initiate translation at the uORF1 start codon, encode a short polypeptide, and then readily reacquire an eIF2-GTP-Met-tRNA complex in time to reinitiate at the next in-frame uORF2 initiation codon[10][27][30]. Since uORF2 is positioned out-of-frame with the ATF4 coding region, translation of uORF2 terminates upstream of the ATF4 start codon, preventing ATF4 protein synthesis[10][27][30]. Consequently, under basal conditions, ATF4 protein levels are maintained at low levels despite continuous transcription of the ATF4 mRNA.
In contrast, when cells experience stress and eIF2α kinases phosphorylate eIF2α, the concentration of active eIF2-GTP-Met-tRNA ternary complexes drops sharply[7][10][27][30]. Under these reduced ternary complex conditions, ribosomes translating the ATF4 mRNA 5' UTR still efficiently initiate at uORF1 and synthesize the short uORF1 polypeptide[10][27][30]. However, when the scanning ribosome resumes translation after terminating uORF1, it cannot reacquire a new ternary complex rapidly enough at the low ternary complex concentrations, causing it to bypass (re-initiate at) the out-of-frame uORF2 initiation codon and instead scan to and initiate at the downstream ATF4 main coding region[10][27][30]. This mechanism, termed "delayed translation reinitiation," represents a remarkable evolutionary solution where the very same stress signal that shuts down global protein synthesis simultaneously and selectively upregulates ATF4 translation[10][27][30]. The optimal distance between uORF1 and uORF2 is critical to this mechanism—experimental insertion of sequences between these elements that extends the intervening distance prevents efficient ATF4 translation even under stress conditions[30].
ATF4 regulates an extensive network of target genes involved in amino acid metabolism, oxidative stress resistance, autophagy, apoptosis, cell differentiation, angiogenesis, and developmental processes[1][2][6][9][15][18][22][35]. ChIP-sequencing studies in multiple cell types have identified ATF4 binding sites near the promoters of hundreds of genes, and genome-wide transcriptomic analysis combined with ChIP data reveals approximately 1,955 genes that show both ATF4 occupancy and ATF4-dependent differential expression[18][28]. Pathway enrichment analysis of ATF4 target genes demonstrates significant enrichment for processes directly related to stress amelioration and cellular adaptation, including endoplasmic reticulum stress response, amino acid metabolism and synthesis, oxidative stress response, autophagy and mitophagy, and apoptosis[6][15][18].
Among the most extensively characterized ATF4 target genes is asparagine synthetase (ASNS), which catalyzes the synthesis of asparagine from aspartate during amino acid starvation[9][14]. ASNS induction by amino acid deprivation occurs exclusively through the GCN2-eIF2α-ATF4 pathway, as ATF4-deficient cells show completely blocked ASNS induction under amino acid limitation[9]. The ASNS promoter contains C/EBP-ATF response elements (CARE) that serve as amino acid response elements (AARE) recognized by ATF4[9]. ATF4 rapidly translocates to the nucleus within 30-45 minutes of amino acid limitation and associates with the ASNS promoter, with maximal binding occurring around 4 hours, coinciding with peak ASNS transcription[9]. However, sustained amino acid limitation beyond this point results in ATF4-dependent induction of ATF3, C/EBPβ, and CHOP proteins, which subsequently recruit to the ASNS CARE site and progressively suppress ATF4-mediated transcription[9]. This elegant self-limiting mechanism provides temporal control over ASNS expression, preventing indefinite overproduction of the amino acid synthesis enzyme.
Other critical ATF4 target genes include DNA damage-inducible transcript 3 (DDIT3, encoding CHOP), a pro-apoptotic transcription factor induced during prolonged ER stress[18][21]; tribbles pseudokinase 3 (TRIB3), which inhibits the anti-apoptotic kinase Akt[18]; C/EBP family members including C/EBPβ, C/EBPγ, and C/EBPδ[18]; autophagy-related genes (ATG genes) including ATG9, ATG12, ATG101, and others that comprise the autophagic machinery[8]; oxidative stress response genes including genes of the glutathione pathway such as cystathionine γ-lyase (CTH) and the xc− amino acid transporter solute carrier family 7 member 11 (SLC7A11)[2][15]; amino acid transporter genes including SLC1A4, SLC38A2, SLC3A2, and others involved in system A, ASC, L, N, T, and xc− transport systems[2][42]; and protein phosphatase 1 regulatory subunit 15A (PP1R15A, also known as GADD34), which provides negative feedback by dephosphorylating eIF2α, thereby terminating the ISR[2][15]. Additionally, ATF4 directly activates NLRP1 inflammasome component expression during ER stress, establishing a direct mechanistic link between ER stress and inflammasome-mediated innate immunity[31][34].
The specific subset of ATF4 target genes activated in response to a particular stress stimulus is highly dependent on the stress type, cellular context, and the particular combinations of ATF4 dimerization partners present[11][18][28]. For example, during amino acid starvation induced through GCN2 activation, ATF4 preferentially regulates genes involved in amino acid synthesis and transport, promoting cellular adaptation to the nutrient limitation[9][42]. In contrast, when ER stress activates the ISR through PERK-mediated eIF2α phosphorylation, ATF4 instead coordinately activates both adaptive genes including protein chaperones and genes encoding ERAD machinery components (which are shared with amino acid starvation responses), but also uniquely activates XBP1 and ATF6, other principal UPR transcription factors[11][15]. The duration and intensity of the stress also critically determines whether ATF4 drives a pro-survival transcriptional program or a pro-apoptotic one[11][18][28]. Low-intensity or brief ISR activation preferentially induces survival-promoting genes involved in stress amelioration and cellular recovery[11]. However, if stress is severe in intensity or prolonged in duration, overwhelming the cell's adaptive capacity, ATF4 cooperates with CHOP to activate pro-apoptotic target genes including BCL2-interacting mediator of cell death (BIM), p53 upregulated modulator of apoptosis (PUMA), Noxa, and others that trigger programmed cell death[11][18][28].
ATF4 is subject to extensive post-translational modifications that modulate its transcriptional activity, protein stability, subcellular localization, and ability to form productive heterodimeric complexes[11][28][52][57]. Phosphorylation represents one of the most significant regulatory PTM for ATF4, occurring at multiple serine and threonine residues throughout both the TAD and bZip domains[11][28][57]. Casein kinase 2 (CK2) phosphorylates ATF4 at serine 215 within the TAD, and this phosphorylation significantly enhances ATF4 transcriptional activity[11][28][52]. Mutation of serine 215 to alanine (S215A) substantially reduces reporter activity driven by amino acid response elements or the ATF3 promoter[11][28][52]. Importantly, mutagenesis studies demonstrated that only the bZip alpha helix of ATF4 is highly ordered, with CK2 requiring the bZip domain structure to phosphorylate ATF4 in the otherwise disordered transactivation domain region[11][28][52].
Another significant phosphorylation occurs at serine 219, which is critical for recognizing ATF4 as a substrate for proteasomal degradation[11][25][28][52]. This phosphorylation is catalyzed by glycogen synthase kinase 3 (GSK3), particularly in pancreatic β-cells[11][28][52]. The functional significance of this phosphorylation became apparent when researchers discovered that insulin signaling, which inhibits GSK3, resulted in unexpected ATF4 upregulation in pancreatic cells[11][28][52]. This regulatory relationship connects insulin/glucose sensing to ATF4 activity, potentially allowing cells to couple nutrient sensing through insulin signaling with stress response pathways. Additionally, the RET kinase phosphorylates ATF4 at threonine residues 107, 114, 115, and 119, which reduces transcription of pro-apoptotic target genes NOXA and PUMA, though it remains unclear whether this represents a general reduction in ATF4 transcriptional activity or specific suppression of pro-apoptotic targets[11][28][52].
The SCF^βTRCP^ E3 ubiquitin ligase complex mediates phosphorylation-dependent ubiquitination and proteasomal degradation of ATF4[11][25][28][52][57]. The β-transducin repeat-containing protein (βTRCP) component of this complex recognizes the motif DSGXXXS located at ATF4 serine residues 219 and 224, a recognition sequence similar to those found in other SCF^βTRCP^ substrates including IκBα and β-catenin[25]. The F-box-deleted βTRCP protein acts as a dominant-negative inhibitor that prevents ATF4 ubiquitination and degradation, resulting in enhanced ATF4 stability and increased activity in cyclic AMP-mediated transcription[25]. The in vivo ubiquitination assay revealed that presence of wild-type βTRCP significantly enhances ATF4 ubiquitination, with higher-molecular-weight polyubiquitinated forms detected only upon longer exposure, suggesting that ATF4 may be preferentially targeted for monoubiquitination rather than traditional polyubiquitin chain-mediated proteasomal degradation[25]. The protein EP300 histone acetyltransferase associates with ATF4's N-terminal region to prevent ubiquitination, operating independently of EP300's acetylation catalytic activity, suggesting that physical binding of EP300 to ATF4 sterically blocks N-terminal ubiquitination sites[11][28][57].
Several E3 ubiquitin ligase adaptor proteins have been identified as ATF4-interacting proteins, including ASB7 (ankyrin repeat and SOCS box-containing protein 7) and MDM2, which may participate in ubiquitinating ATF4 at N-terminal sites[11][28][57]. These regulatory mechanisms suggest that ATF4 protein abundance is tightly controlled through a balance between stabilization by certain proteins (EP300) and degradation promoted by others (βTRCP, potentially ASB7, and MDM2), allowing cells to rapidly adjust ATF4 protein levels in response to changing cellular conditions and the need for stress response activation or termination.
Beyond phosphorylation and ubiquitination, ATF4 undergoes several other PTMs including SUMOylation at lysine residues 45 and 53, which can compete with ubiquitination at the same sites, potentially regulating whether ATF4 is ubiquitinated for degradation or SUMOylated for altered function[11][28][57]. Acetylation of ATF4 has also been detected in multiple studies, though the specific lysine residues modified and the functional consequences of acetylation remain to be fully elucidated[11][28][57]. These multiple PTMs at distinct sites within ATF4 provide numerous regulatory nodes through which cellular signaling cascades can modulate ATF4 activity, explaining the plasticity in ATF4 function across different stress contexts and cellular types.
Twenty-seven bZIP transcription factors have been identified and verified as direct ATF4-interacting heterodimerization partners through techniques including Förster resonance energy transfer (FRET) measurements of purified proteins[11][28][57]. These include multiple members of the C/EBP family (C/EBPα, C/EBPβ, C/EBPγ, C/EBPδ), ATF family members (ATF3, ATF5, ATF6), AP-1 family members (c-Jun, c-Fos, Fra1, Fra2), and others[11][28][57]. The specific ATF4 heterodimer that forms substantially influences both the set of target genes activated and the magnitude of transcriptional response[11][18][28]. For instance, ATF4-CHOP heterodimers are particularly effective at activating pro-apoptotic genes during prolonged ER stress[11][18], while ATF4-C/EBPβ heterodimers preferentially regulate amino acid metabolic genes during nutrient stress[9]. ATF4-ATF3 heterodimers were found to bind and upregulate the pro-apoptotic protein NOXA/PMAIP1[10][18].
The CREB3L2-ATF4 heterodimer has recently emerged as particularly important in neurodegenerative disease contexts, specifically in Alzheimer's disease pathogenesis[26]. In this pathway, amyloid-beta 42 (Aβ42), an early trigger of Alzheimer's disease pathogenesis, potentiates the heterodimerization of CREB3L2 with ATF4[26]. Using a novel chemogenetic methodology termed ChIPmera (developed to resolve the genomic binding patterns of specific dimeric transcription factors), researchers demonstrated that the CREB3L2-ATF4 heterodimer regulates a transcription network that interacts with approximately half of the genes differentially expressed in Alzheimer's disease, including genes associated with β-amyloid and tau neuropathologies[26]. Importantly, this heterodimer triggers characteristic cellular features of Alzheimer's disease including tau hyperphosphorylation, a primary driver of neurodegeneration in the condition[26].
Beyond heterodimerization with other bZIP transcription factors, ATF4 physically interacts with several non-bZIP proteins that modulate its function[11][28][57]. The pseudokinase TRIB3 directly interacts with ATF4 and inhibits its transcriptional activity, as well as that of CHOP and C/EBPβ[18][28]. The chromatin architecture regulator CTCF has been identified as an ATF4-interacting protein, and this interaction may confer additional plasticity to the genome to facilitate large-scale reorganization of the transcriptome during stress[18][28]. In neurons, the DISC1 (disrupted in schizophrenia 1) protein binds ATF4 and inhibits its transcription factor activity by disrupting ATF4 dimerization and DNA-binding capability[21][28]. This interaction appears particularly important for regulating synaptic plasticity and long-term memory, as DISC1 acts as a regulator of synaptic functions by preventing ATF4-mediated transcription[21]. The DAPK3 (death-associated protein kinase 3) protein also interacts with ATF4, with evidence suggesting that ATF4 dimerization with DAPK3 prevents DAPK3 homodimerization and thereby inhibits its kinase activity-dependent apoptosis induction[18].
ATF4 functions exclusively as a nuclear transcription factor, requiring proper trafficking to the nucleus to execute its transcriptional roles[14][17][21]. A nuclear localization sequence (NLS) has been identified within the C-terminal region of the ATF4 protein[14]. Early observations suggested that endogenous ATF4 undergoes rapid translocation to the nucleus following synthesis during stress conditions[14]. However, subsequent experimentation revealed that ATF4 trafficking to the nucleus does not require additional signals from the integrated stress response pathway itself—ectopically expressed ATF4 protein accumulates predominantly in the nuclear compartment even in the absence of stress and without activation of the eIF2α phosphorylation cascade[14]. This indicates that the NLS within ATF4 is sufficient for constitutive nuclear localization, and that the stress-responsive element in ATF4 regulation is primarily translational rather than translocation-dependent[14]. The nuclear localization of ATF4 appears to occur rapidly, as most newly synthesized ATF4 protein localizes to the nucleus within minutes of synthesis[14]. ATF4 associates with chromatin and exists within protein-containing complexes and nuclear speck structures, indicating that it maintains stable interactions with other transcriptional and regulatory machinery[17][24][28].
During amino acid starvation or ER stress, ATF4 binds to the promoters and enhancers of target genes with kinetics that reflect the stress intensity and duration[9]. ChIP analysis demonstrated that ATF4 binding to the ASNS gene promoter peaks at approximately 4-6 hours of amino acid starvation, with binding gradually declining between 4 and 24 hours as feedback regulatory proteins including ATF3, C/EBPβ, and CHOP accumulate and compete for binding sites[9]. Circadian regulation represents an additional layer of ATF4 nuclear dynamics—ATF4 binds in a circadian time-dependent manner to CRE elements in the promoters of the core clock component PER2 and the serotonin transporter SLC6A4, periodically activating their transcription in a time-of-day-dependent manner[2][21][24].
ATF4 serves as the master regulator of amino acid biosynthesis and cellular amino acid homeostasis during nutrient stress[2][8][9]. During amino acid deprivation, ATF4 upregulates expression of amino acid biosynthetic enzymes and amino acid transporter proteins to increase intracellular amino acid availability[2][8][9]. The asparagine synthetase (ASNS) gene represents the paradigmatic example, with ATF4 binding to AARE sequences and robustly activating transcription in response to amino acid limitation[9]. In amino acid-deprived cancer cells or tumors in nutrient-poor microenvironments, ATF4-dependent ASNS upregulation maintains cellular asparagine levels, enabling continued protein synthesis and cell survival[9][35]. Similarly, ATF4 directly activates transcription of amino acid transporter genes from multiple transport systems, increasing the cellular capacity to capture available amino acids from the extracellular environment[2][42]. The ATF4-dependent amino acid transporter reprogramming has been particularly well-characterized in the context of tryptophan deprivation, where ATF4 upregulates expression of SLC1A5, SLC7A11, and SLC1A4 to enhance transport of glutamine, cystine, and other amino acids that can compensate for tryptophan limitation[39].
Beyond amino acid metabolism, ATF4 is crucial for cellular adaptation to oxidative stress through upregulation of antioxidant genes and redox-balancing pathways[2][15][21]. ATF4 transcriptionally activates the glutathione biosynthetic pathway by inducing expression of multiple enzymes including cystathionine γ-lyase (CTH) and glutamate-cysteine ligase catalytic subunit (GCLC)[15]. Glutathione (GSH), the product of these biosynthetic pathways, serves as the critical reducing substrate for glutathione peroxidase 4 (GPX4), the key enzyme protecting cells from ferroptotic cell death[15][41]. Additionally, ATF4 regulates expression of system xc− amino acid transporters (SLC7A11 and SLC3A2) that mediate cystine/glutamate exchange, thereby maintaining cystine uptake which is required for glutathione synthesis[2][15][39]. This multifaceted ATF4-dependent regulation of redox homeostasis represents a critical adaptation to oxidative stress, linking amino acid transport, amino acid biosynthesis, and antioxidant enzyme expression into a coordinated transcriptional program.
ATF4 orchestrates the induction of autophagy during amino acid starvation and ER stress through direct transcriptional activation of multiple autophagy-related genes (ATG genes)[8]. The eIF2α-ATF4 pathway directs a comprehensive autophagy gene transcriptional program by binding to AARE sequences in the promoters of genes including ATG9, ATG12, ATG101, and many others encoding components of the autophagosome biogenesis, elongation, and function machinery[8]. ATF4 and CHOP function cooperatively to increase transcription of the autophagy adaptor protein p62/SQSTM1, with both transcription factors binding AARE sequences in the p62 promoter[8]. The ATF4-dependent induction of autophagy during nutrient deprivation represents an adaptive response allowing cells to degrade intracellular components for amino acid recycling and energy production, supporting survival during prolonged nutrient limitation.
During ER stress, ATF4 also plays a critical role in regulating mitochondrial function and bioenergetics[55]. The PERK-eIF2α-ATF4 axis specifically increases expression of supercomplex assembly factor 1 (SCAF1, also designated COX7A2L), which promotes formation of respiratory chain supercomplexes and enhances mitochondrial oxidative phosphorylation[55]. This ATF4-mediated increase in mitochondrial energetic capacity appears particularly important for providing the ATP required for active unfolded protein response and protein synthesis recovery during ER stress[55]. Additionally, ATF4 activates transcription of mitochondrial chaperone proteins including the mitochondrial heat shock protein 70 (HSPA9) and proteases such as the AAA+ protease LON, which enhance mitochondrial protein quality control and proteostasis capacity[40]. Some ATF4 target genes localize to the mitochondria and regulate apoptosis signaling, including the chaperone DNAJA3/TID1 which exists in both long and short isoforms with opposing roles in apoptosis regulation[18].
ATF4 plays indispensable roles in skeletal development and bone homeostasis through its expression in osteoblasts[20][50][53][56][59]. Global ATF4 deletion in mice results in severe osteopenia, impaired osteoblast terminal differentiation, reduced osteocalcin (OCN) expression, and decreased type I collagen synthesis[20][50]. The Atf4 null mouse skeleton exhibits a characteristically smaller size due to reduced cartilage growth and delayed ossification center formation[20]. Conditional genetic approaches revealed that ATF4 operates through distinct cell-autonomous functions in both chondrocytes and osteoblasts. In chondrocytes, ATF4 regulates expression of Indian hedgehog (Ihh), a paracrine signaling molecule that controls proliferation of prechondrogenic cells and stimulates osteoblast differentiation in the adjacent perichondrium[20]. Atf4 null chondrocytes exhibit reduced Ihh expression and impaired hedgehog signaling, leading to secondary defects in osteoblast differentiation and bone collar formation[20]. Through selective overexpression of Atf4 in chondrocytes of otherwise Atf4-null mice, the full bone formation phenotype can be rescued, demonstrating that chondrocyte-derived Atf4 dominates in controlling early osteogenesis during skeletal development[20].
In mature osteoblasts, ATF4 functions as a critical regulator during terminal differentiation and matrix mineralization[50][53][56][59]. ATF4 acts as a substrate for the ribosomal S6 kinase RSK2 (encoded by RPS6KA3), and this phosphorylation substantially enhances ATF4 transactivation activity and promotes expression of osteoblast-specific genes including osteocalcin (BGLAP), osteopontin (SPP1/IBSP), alkaline phosphatase (ALP), and type I collagen (COL1A1)[50][53]. Importantly, ATF4 post-transcriptionally regulates the synthesis of type I collagen, the main constituent of the bone matrix, through mechanisms that remain to be fully elucidated[50][53]. The cooperation between ATF4 and the master osteogenic transcription factor RUNX2 represents a key regulatory axis, with RUNX2 promoting expression of ATF4, which then acts downstream to amplify osteoblast differentiation signals[50][53].
ATF4 and the FOXO1 transcription factor cooperate in osteoblasts to regulate glucose homeostasis, with implications extending far beyond bone itself[56][59]. Both FoxO1 and ATF4 suppress osteocalcin activity through upregulating expression of protein tyrosine phosphatase (encoded by Esp), which inactivates osteocalcin through carboxylation[56][59]. This FoxO1/ATF4-mediated suppression of osteocalcin bioactivity decreases insulin secretion from pancreatic β-cells and reduces insulin sensitivity in liver, adipose tissue, and muscle[56][59], thereby increasing blood glucose levels and decreasing glucose tolerance[56][59]. Genetic models demonstrate that FoxO1 and ATF4 cooperate synergistically in this regulatory pathway—compound heterozygous FoxO1^+/−^;Atf4^+/−^ mice with single allele deletions of both genes show metabolic phenotypes similar to complete knockouts of either factor alone[56]. This reveals an elegant cross-talk between bone and systemic energy metabolism, with osteoblast-expressed ATF4 contributing critically to whole-body glucose homeostasis.
ATF4 is essential for the survival and function of the avascular lens, which relies entirely on diffusion for nutrient delivery and depends critically on amino acid and glutathione availability[45][48]. Atf4 null embryos exhibit severe lens defects starting in late embryonic development, with complete lens disintegration observed by birth due to epithelial and/or fiber cell apoptosis[45][48]. The mechanism underlying this developmental requirement involves ATF4's role in regulating nutrient transport and biosynthesis genes critical for lens cell survival in its avascular environment[45]. RNA-sequencing analysis of Atf4 null lenses revealed enrichment for genes involved in nutrient transport, amino acid biosynthesis, and tRNA charging[45]. These changes result in marked reductions in lens free amino acid and glutathione levels, leading to diminished extractable lens protein and ultimately lens disintegration[45]. The lens epithelial cells in Atf4 null lenses show dramatically reduced proliferation rates—fewer than 20% of null lens epithelial cells are actively cycling compared to over 50% in wildtype lenses[45]. This demonstrates that ATF4, through its integrated stress response functions, is critical for mediating lens cell adaptation to the metabolic constraints imposed by avascularity and maintaining the optical transparency necessary for vision.
ATF4 plays important roles in hematopoietic stem cell (HSC) homeostasis and immune cell development[23][32]. ATF4 deficiency leads to aging-like attrition of adult hematopoietic stem cells, characterized by functional defects including reduced repopulating and self-renewal capacities and myeloid differentiation bias[23]. ATF4-deficient HSCs show phenotypic expansion with increased frequencies of long-term HSCs, reminiscent of aged hematopoietic stem cell populations, indicating that ATF4 normally acts to prevent HSC aging-related alterations[23]. This ATF4-dependent regulation of HSC aging involves control of mitochondrial reactive oxygen species production through targeting HIF1α[23]. Mechanistically, loss of ATF4 in HSCs leads to elevated mitochondrial ROS production, compromising the self-renewal and repopulating capacity of these cells[23]. ATF4 also regulates CD4+ T cell immune responses through metabolic reprogramming, controlling the expression of genes involved in amino acid intake, mTORC1 activation, protein translation, and de novo amino acid synthesis[32]. ATF4-deficient CD4+ T cells show defects in redox homeostasis, proliferation, differentiation, and cytokine production[32]. ATF4-deficient mice mount reduced Th1 but elevated Th17 immune responses and develop more severe experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis[32]. These findings establish ATF4 as a critical regulator of both innate hematopoietic stem cell function and adaptive immune cell differentiation and function.
ATF4 is frequently upregulated in cancer cells and tumors, and emerging evidence indicates that ATF4 plays complex roles in cancer progression through regulation of amino acid metabolism and metabolic reprogramming[22][35]. In numerous cancer types, ATF4-mediated upregulation of amino acid biosynthetic enzymes including asparagine synthetase and phosphoserine aminotransferase 1 (PSAT1) enables cancer cells to synthesize amino acids de novo when exogenous supply is limited[22][35]. This ATF4-dependent amino acid biosynthetic capacity is particularly important in nutrient-poor tumor microenvironments where certain amino acids become limiting. PSAT1 represents a critical downstream target of ATF4 in estrogen receptor-negative breast cancer, where ATF4-dependent PSAT1 upregulation enhances cell proliferation through the GSK3β/β-catenin/cyclin D1 signaling pathway[22]. In gastric cancer, ATF4 has been found to participate in cancer initiation and progression through multiple mechanisms, including direct activation of the Sonic Hedgehog pathway (through binding to the SHH promoter) and upregulation of CHAC1 glutathione-specific γ glutamylcyclotransferase to degrade glutathione and mediate ferroptosis[22].
Paradoxically, while ATF4-mediated amino acid biosynthesis can support tumor growth in certain contexts, loss of ATF4 can increase susceptibility to ferroptosis and impair tumor development in others[22]. This dual role likely depends on the specific metabolic context and the particular cancer type. In hepatocellular carcinoma (HCC), ATF4 directly targets SLC7A11 (encoding the xc− amino acid transporter) to sustain glutathione synthesis and prevent ferroptosis-dependent cell death[22]. Therefore, ATF4 ablation could increase HCC susceptibility to ferroptosis and potentially impair tumorigenesis[22]. In glioblastoma, ATF4 modulates metabolic reprogramming, integrated stress response, and ferroptosis regulation to promote disease progression[22]. ATF4 can promote ferroptosis-mediated cell death and tumor angiogenesis in glioma, effects that are attenuated by xCT (SLC7A11) inhibition and can be further abrogated by the ferroptosis inducer erastin[22]. Thus, ATF4 ablation has been proposed as a promising target for suppressing glioma growth and vasculature by sensitizing glioma cells to ferroptosis[22].
In castration-resistant prostate cancer (CRPC), loss of the protein kinase C iota/lambda (PKCλ/ι) activates mTORC1 to induce an ATF4-mediated transcriptional program, leading to metabolic adaptation of CRPC cells to elevate the flux through the one-carbon pathway[22]. This metabolic reprogramming driven by PKCλ/ι loss and ATF4 activation appears to provide selective growth advantages to CRPC cells. These findings demonstrate that ATF4 functions at the hub of a complex metabolic reprogramming network in cancer, and that the outcome (tumor promotion or suppression) depends on the interplay between ATF4 activation and other metabolic signaling pathways operating in the specific cancer type.
Recent research has highlighted ATF4's role in Alzheimer's disease pathogenesis through its interaction with CREB3L2, as discussed above[26]. The CREB3L2-ATF4 heterodimer transcriptionally regulates genes involved in cellular proteostasis and protein trafficking, and dysregulation of this axis may contribute to the protein aggregation and tau hyperphosphorylation characteristic of Alzheimer's disease[26]. Additionally, ATF4 has been implicated in other neurodegenerative conditions through its role in regulating synaptic plasticity and long-term memory[21][28]. ATF4 normally acts as a repressor of synaptic plasticity, inhibiting the induction and maintenance of long-term memory through its interaction with DISC1, which disrupts ATF4 dimerization and DNA binding[21][28]. This repressive role of ATF4 in memory formation appears to be a conserved function, as ATF4 in C. elegans (where the IMPACT protein regulates ATF4) has been shown to promote lifespan extension[4][21].
The critical role of ATF4 in osteoblast differentiation and bone homeostasis places it at the center of several skeletal disorders[50][53]. Mutations or dysregulation of ATF4 or its upstream regulators can lead to impaired bone formation and osteopenia[50][53]. The discovery that ATF4 cooperates with FOXO1 to regulate glucose homeostasis through osteoblasts has opened new perspectives on the skeletal contributions to metabolic diseases including obesity and diabetes[56][59]. Understanding ATF4 regulation in osteoblasts may provide new therapeutic opportunities for treating metabolic disorders through bone-targeted interventions.
ATF4's role in regulating glucose homeostasis through osteoblast expression indicates that ATF4 dysregulation may contribute to metabolic diseases[56][59]. The discovery of insulin signaling-dependent ATF4 upregulation through GSK3 inhibition suggests that ATF4 may serve as a link between nutrient sensing (via insulin signaling) and stress response pathways[11][28][52]. This positioning of ATF4 at the interface of nutrient sensing and stress responses may make it an important regulator in metabolic disease contexts where cells experience combined nutritional and metabolic stress.
Activating Transcription Factor 4 (ATF4) represents a masterfully evolved cellular regulatory hub that coordinates diverse aspects of mammalian physiology ranging from acute cellular stress adaptation to long-term developmental processes and systemic metabolic homeostasis. The intricate molecular mechanisms underlying ATF4 function—including its sophisticated translational control through upstream open reading frames, its context-dependent heterodimerization with numerous bZIP partners, its extensive post-translational modifications, and its selective target gene activation—exemplify how cells achieve remarkable specificity and plasticity in gene regulation using relatively simple molecular components. ATF4's dual functionality as both a basal metabolic regulator essential for normal development and tissue homeostasis, and a stress-responsive transcription factor capable of both cell survival and cell death decisions, demonstrates the evolutionary success of this protein as a central molecular decision point in cellular physiology. The extensive research into ATF4 function has revealed its involvement in virtually every major cellular and organismal process including amino acid metabolism, oxidative stress response, autophagy, apoptosis, development, hematopoiesis, immune function, bone homeostasis, energy metabolism, and disease pathogenesis. Future research directions include clarifying the precise molecular mechanisms underlying ATF4's role in specific diseases, understanding how ATF4 coordinates with other stress-response pathways at the systems level, developing therapeutic strategies to modulate ATF4 activity for disease treatment, and elucidating the full spectrum of ATF4 target genes and their functional relationships. The continuing discovery of new ATF4 interaction partners, target genes, and regulatory modifications indicates that despite decades of research, fundamental aspects of ATF4 biology remain to be uncovered, promising continued insights into how this elegant transcription factor orchestrates cellular adaptation and survival.
id: P18848
gene_symbol: ATF4
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: ATF4 (Activating Transcription Factor 4) is a bZIP transcription
factor that serves as the central effector of the Integrated Stress Response
(ISR). Under basal conditions, ATF4 translation is suppressed by upstream open
reading frames (uORFs) in its 5'UTR. Upon cellular stress (ER stress, amino
acid deprivation, oxidative stress, mitochondrial stress), phosphorylation of
eIF2alpha by stress-sensing kinases (PERK, GCN2, HRI, PKR) leads to
preferential translation of ATF4. In the nucleus, ATF4 heterodimerizes with
other bZIP transcription factors (CHOP/DDIT3, C/EBP family members, CREB,
ATF3) via its leucine zipper domain and binds to cAMP response elements (CRE)
and C/EBP-ATF response elements (CARE/AARE) to activate transcription of
stress-responsive genes involved in amino acid metabolism (ASNS, SLC7A11),
redox homeostasis, autophagy, and apoptosis. ATF4 also plays non-stress roles
in osteoblast differentiation and bone development.
existing_annotations:
- term:
id: GO:0000977
label: RNA polymerase II transcription regulatory region sequence-specific
DNA binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF4 is a bZIP transcription factor that binds to CRE and
CARE/AARE sequences in promoters to regulate transcription. This
molecular function annotation is appropriate and consistent with its
well-established role as a sequence-specific DNA-binding transcription
factor.
action: ACCEPT
reason: ATF4's binding to specific regulatory sequences (CRE, CARE/AARE)
is extensively documented and represents a core molecular function
(PMID:12871976, PMID:11960987).
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- reference_id: file:human/ATF4/ATF4-deep-research-cyberian.md
supporting_text: 'model: deep-research'
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF4 functions predominantly as a transcriptional activator for
stress-responsive genes including ASNS, GRP78/BiP, CHOP, and TRB3. This
annotation accurately reflects its primary molecular function.
action: ACCEPT
reason: ATF4's transcriptional activator function is well-documented.
Overexpression of ATF4 increases promoter-driven transcription of target
genes (PMID:11960987, PMID:12871976).
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF4 localizes to the nucleus where it functions as a
transcription factor. Nuclear localization has been demonstrated by
multiple experimental approaches.
action: ACCEPT
reason: Nuclear localization is essential for ATF4's function as a
transcription factor and is well-documented (UniProt, PMID:23123191,
PMID:16682973).
supported_by:
- reference_id: PMID:23123191
supporting_text: Functional interaction of protein kinase CK2 and
activating transcription factor 4 (ATF4), a key player in the
cellular stress response.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF4 regulates transcription of numerous genes in response to
cellular stress. This biological process annotation captures its core
function.
action: ACCEPT
reason: Regulation of pol II transcription is a central function of ATF4,
documented extensively in the ISR and stress response literature.
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- term:
id: GO:1990589
label: ATF4-CREB1 transcription factor complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF4 forms heterodimeric complexes with CREB1 to regulate target
gene expression. This complex was identified in the context of GRP78/BiP
regulation.
action: ACCEPT
reason: ATF4-CREB1 complex formation is documented experimentally
(PMID:12871976). The IBA annotation is consistent with this evidence.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:1990590
label: ATF1-ATF4 transcription factor complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF4 forms heterodimeric complexes with ATF1. This was
demonstrated in the context of stress-induced transcription.
action: ACCEPT
reason: ATF4-ATF1 complex formation is documented (PMID:12871976).
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0003677
label: DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: ATF4 binds DNA as part of its transcription factor activity. This
is a general term appropriate for IEA evidence.
action: ACCEPT
reason: DNA binding is well-established for ATF4 as a bZIP transcription
factor. The more specific term GO:0000977 is also annotated with better
evidence.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: ATF4 is a well-established transcription factor. This IEA
annotation is consistent with experimental evidence.
action: ACCEPT
reason: Transcription factor activity is a core function of ATF4,
confirmed by multiple experimental studies.
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Nuclear localization is well-established for ATF4. Duplicate of
IBA annotation.
action: ACCEPT
reason: Consistent with IBA annotation and experimental evidence.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: ATF4 is synthesized in the cytoplasm and can shuttle between
cytoplasm and nucleus. Under stress, ATF4 accumulates in the nucleus,
but cytoplasmic localization is part of its normal biology.
action: ACCEPT
reason: ATF4 is translated in the cytoplasm and can localize there under
basal conditions before stress-induced nuclear accumulation (UniProt).
- term:
id: GO:0005813
label: centrosome
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: ATF4 has been reported to localize to the centrosome based on
interaction with NEK6 and colocalization studies. This appears to be a
non-canonical localization.
action: KEEP_AS_NON_CORE
reason: While documented (PMID:20873783), centrosomal localization is not
central to ATF4's primary function as a stress-response transcription
factor.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: ATF4 plasma membrane localization may relate to interaction with
GABA-B receptors in neurons (by similarity to rat). This is a
specialized context.
action: KEEP_AS_NON_CORE
reason: Membrane localization via GABBR interaction is a specialized
neuronal function, not the core stress-response role.
- term:
id: GO:0006351
label: DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: ATF4 participates in DNA-templated transcription as a
transcription factor. This is a broad annotation appropriate for IEA.
action: ACCEPT
reason: Consistent with ATF4's role as a transcription factor.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: ATF4 regulates transcription of stress-responsive genes. This is
a core function.
action: ACCEPT
reason: Consistent with ATF4's established role as a transcriptional
regulator.
- term:
id: GO:0016607
label: nuclear speck
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: ATF4 can be recruited to nuclear speckles following interaction
with EP300/p300.
action: KEEP_AS_NON_CORE
reason: Nuclear speckle localization is context-dependent and related to
EP300 interaction (PMID:16219772), not a primary localization.
- term:
id: GO:0042981
label: regulation of apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: ATF4, particularly in partnership with CHOP, can regulate
apoptosis during prolonged ER stress. However, this is an outcome of
chronic stress signaling rather than ATF4's primary function.
action: KEEP_AS_NON_CORE
reason: ATF4's pro-apoptotic role is context-dependent (chronic stress
with CHOP) and represents a downstream consequence rather than core
function.
- term:
id: GO:0048511
label: rhythmic process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: ATF4 has been implicated in circadian regulation of gene
expression through binding to CRE elements in clock gene promoters.
action: KEEP_AS_NON_CORE
reason: While ATF4 can regulate circadian genes, this is a secondary
function not central to its ISR role.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11238952
review:
summary: ATF4 interacts with BTRC (beta-TrCP) as part of the SCF ubiquitin
ligase complex that targets ATF4 for degradation. This is a functionally
relevant interaction.
action: MODIFY
reason: Protein binding is too vague. The specific interaction is with
BTRC as a substrate of the SCF ubiquitin ligase for proteasomal
degradation.
proposed_replacement_terms:
- id: GO:0031625
label: ubiquitin protein ligase binding
supported_by:
- reference_id: PMID:11238952
supporting_text: ATF4 degradation relies on a
phosphorylation-dependent interaction with the SCF(betaTrCP)
ubiquitin ligase.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12743605
review:
summary: Interaction with TRIB3, a pseudokinase that inhibits ATF4
transactivation activity.
action: MODIFY
reason: The interaction with TRIB3 represents a specific regulatory
mechanism. A more specific term would be preferred.
proposed_replacement_terms:
- id: GO:0140297
label: DNA-binding transcription factor binding
supported_by:
- reference_id: PMID:12743605
supporting_text: SKIP3, a novel Drosophila tribbles ortholog, is
overexpressed in human tumors and is regulated by hypoxia.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12812986
review:
summary: Interaction with DISC1 (Disrupted in Schizophrenia 1). DISC1
inhibits ATF4 by disrupting its dimerization and DNA-binding.
action: MODIFY
reason: This represents a specific regulatory interaction affecting ATF4
transcription factor activity.
proposed_replacement_terms:
- id: GO:0140297
label: DNA-binding transcription factor binding
supported_by:
- reference_id: PMID:12812986
supporting_text: 'DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated
protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation
and loss of interaction with mutation.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12860379
review:
summary: Interaction with RPB3 (POLR2C), a subunit of RNA polymerase II.
This reflects ATF4's function as a transcription factor.
action: MODIFY
reason: This is a functionally relevant interaction with the transcription
machinery.
proposed_replacement_terms:
- id: GO:0140296
label: general transcription initiation factor binding
supported_by:
- reference_id: PMID:12860379
supporting_text: Functional interaction of the subunit 3 of RNA
polymerase II (RPB3) with transcription factor-4 (ATF4).
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16169070
review:
summary: High-throughput interaction study. Generic protein binding
annotation from large-scale study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study lacks functional
specificity.
supported_by:
- reference_id: PMID:16169070
supporting_text: 'A human protein-protein interaction network: a resource
for annotating the proteome.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16189514
review:
summary: High-throughput Y2H study. Generic protein binding annotation.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study lacks functional context.
supported_by:
- reference_id: PMID:16189514
supporting_text: Towards a proteome-scale map of the human
protein-protein interaction network.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16343488
review:
summary: Interaction with CREBZF (Zhangfei). Cooperative transactivation
of CRE.
action: MODIFY
reason: This is a specific interaction between bZIP transcription factors.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:16343488
supporting_text: 2005 Dec 6. Cooperative interaction of Zhangfei and
ATF4 in transactivation of the cyclic AMP response element.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18330356
review:
summary: High-throughput Y2H study. Generic protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:18330356
supporting_text: Construction and characterization of a normalized
yeast two-hybrid library derived from a human protein-coding clone
collection.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19164757
review:
summary: Interaction with ATF3 in the context of ER stress response.
action: MODIFY
reason: ATF3 is a bZIP transcription factor partner of ATF4.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:19164757
supporting_text: ERAD inhibitors integrate ER stress with an
epigenetic mechanism to activate BH3-only protein NOXA in cancer
cells.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19447967
review:
summary: High-throughput interaction mapping study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:19447967
supporting_text: Shifted Transversal Design smart-pooling for high
coverage interactome mapping.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20102225
review:
summary: Coiled-coil array interaction study with viral and cellular bZIP
proteins.
action: MODIFY
reason: These are specific bZIP-bZIP interactions.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:20102225
supporting_text: Identification of bZIP interaction partners of viral
proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20211142
review:
summary: Atlas of transcriptional regulation study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from computational/HT study.
supported_by:
- reference_id: PMID:20211142
supporting_text: An atlas of combinatorial transcriptional regulation
in mouse and man.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20936779
review:
summary: MAP kinase interactome study. Interaction with JUN family.
action: MODIFY
reason: Interaction with JUN represents bZIP heterodimerization.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:20936779
supporting_text: A human MAP kinase interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21408167
review:
summary: Interaction with DAPK2. ATF4 is a substrate of death-associated
protein kinases.
action: MODIFY
reason: This is a kinase-substrate interaction.
proposed_replacement_terms:
- id: GO:0019901
label: protein kinase binding
supported_by:
- reference_id: PMID:21408167
supporting_text: 'New modularity of DAP-kinases: alternative splicing of
the DRP-1 gene produces a ZIPk-like isoform.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21988832
review:
summary: Liver interactome study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:21988832
supporting_text: Toward an understanding of the protein interaction
network of the human liver.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23661758
review:
summary: Systematic bZIP interaction network study. Documents
heterodimerization with multiple bZIP partners.
action: MODIFY
reason: This study specifically characterizes bZIP-bZIP interactions.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions
diversified over a billion years of evolution.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25241761
review:
summary: Proximity ligation assay study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding annotation.
supported_by:
- reference_id: PMID:25241761
supporting_text: Oct 9. Using an in situ proximity ligation assay to
systematically profile endogenous protein-protein interactions in a
pathway network.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: Large-scale proteome interactome mapping.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:25416956
supporting_text: A proteome-scale map of the human interactome
network.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25910212
review:
summary: Study of genetic variant effects on protein interactions.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:25910212
supporting_text: Widespread macromolecular interaction perturbations
in human genetic disorders.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26700459
review:
summary: Interaction with NRF2/NFE2L2 in the context of proteasome
inhibition.
action: MODIFY
reason: ATF4 and NRF2 cooperate in antioxidant response.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:26700459
supporting_text: Involvement of Nrf2 in proteasome inhibition-mediated
induction of ORP150 in thyroid cancer cells.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26871637
review:
summary: Alternative splicing effects on protein interactions.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:26871637
supporting_text: Widespread Expansion of Protein Interaction
Capabilities by Alternative Splicing.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:27107014
review:
summary: Cross-species protein interaction network.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:27107014
supporting_text: An inter-species protein-protein interaction network
across vast evolutionary distance.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
review:
summary: Large-scale interactome study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:28514442
supporting_text: Architecture of the human interactome defines protein
communities and disease networks.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29892012
review:
summary: Interactome perturbation study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:29892012
supporting_text: Jun 11. An interactome perturbation framework
prioritizes damaging missense mutations for developmental disorders.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31413325
review:
summary: Alzheimer's disease interactome study. Interaction with DISC1.
action: MODIFY
reason: DISC1 interaction is functionally relevant for ATF4 regulation.
proposed_replacement_terms:
- id: GO:0140297
label: DNA-binding transcription factor binding
supported_by:
- reference_id: PMID:31413325
supporting_text: HENA, heterogeneous network-based data set for
Alzheimer's disease.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31515488
review:
summary: Genetic variant effects on protein interactions.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:31515488
supporting_text: Extensive disruption of protein interactions by
genetic variants across the allele frequency spectrum in human
populations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Large-scale binary interactome mapping.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:32296183
supporting_text: Apr 8. A reference map of the human binary protein
interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
review:
summary: Neurodegenerative disease protein interactome.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:32814053
supporting_text: Interactome Mapping Provides a Network of
Neurodegenerative Disease Proteins and Uncovers Widespread Protein
Aggregation in Affected Brains.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32911434
review:
summary: NRF2 interactome study. ATF4-NRF2 cooperation in antioxidant
response.
action: MODIFY
reason: Functional interaction between ATF4 and NRF2.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:32911434
supporting_text: Aug 20. A functionally defined high-density NRF2
interactome reveals new conditional regulators of ARE
transactivation.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Cell-specific interactome remodeling study.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding from HT study.
supported_by:
- reference_id: PMID:33961781
supporting_text: 2021 May 6. Dual proteome-scale networks reveal
cell-specific remodeling of the human interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9488481
review:
summary: Interaction with ZIP kinase (DAPK3). ATF4 is phosphorylated by
DAPK3.
action: MODIFY
reason: This is a kinase-substrate interaction.
proposed_replacement_terms:
- id: GO:0019901
label: protein kinase binding
supported_by:
- reference_id: PMID:9488481
supporting_text: ZIP kinase, a novel serine/threonine kinase which
mediates apoptosis.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:16343488
review:
summary: ATF4 can form homodimers through its leucine zipper domain.
action: ACCEPT
reason: ATF4 homodimerization is documented and functionally relevant for
DNA binding.
supported_by:
- reference_id: PMID:16343488
supporting_text: 2005 Dec 6. Cooperative interaction of Zhangfei and
ATF4 in transactivation of the cyclic AMP response element.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:23661758
review:
summary: ATF4 homodimerization confirmed in systematic bZIP interaction
study.
action: ACCEPT
reason: Confirms homodimerization capability.
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions
diversified over a billion years of evolution.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 can act as a transcriptional repressor in certain contexts,
particularly for memory formation in neurons.
action: KEEP_AS_NON_CORE
reason: While ATF4 can repress transcription (e.g., long-term memory
genes), its primary role is as a transcriptional activator in the ISR.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA
binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 binds to CRE and CARE/AARE sequences in pol II-transcribed
genes.
action: ACCEPT
reason: Core molecular function of ATF4.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase
II-specific
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is a pol II transcription factor.
action: ACCEPT
reason: Core molecular function.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 primarily functions as a transcriptional activator.
action: ACCEPT
reason: Core molecular function supported by experimental evidence.
- term:
id: GO:0005667
label: transcription regulator complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 forms complexes with other transcription factors.
action: ACCEPT
reason: ATF4 forms heterodimeric complexes with other bZIP factors.
- term:
id: GO:0007214
label: gamma-aminobutyric acid signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Based on rat ortholog. ATF4 interacts with GABA-B receptors in
neurons.
action: KEEP_AS_NON_CORE
reason: This is a specialized neuronal function, not the core ISR role.
- term:
id: GO:0007623
label: circadian rhythm
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 can regulate circadian gene expression via CRE binding.
action: KEEP_AS_NON_CORE
reason: Circadian regulation is a secondary function.
- term:
id: GO:0008140
label: cAMP response element binding protein binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 heterodimerizes with CREB family members.
action: ACCEPT
reason: Documented interaction with CREB1 (PMID:12871976).
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0009636
label: response to toxic substance
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is activated by various cellular stresses including toxic
insults.
action: KEEP_AS_NON_CORE
reason: General stress response, not specific to toxicants.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 positively regulates stress-responsive genes.
action: ACCEPT
reason: Core function as transcriptional activator.
- term:
id: GO:0030182
label: neuron differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Based on rat ortholog data.
action: KEEP_AS_NON_CORE
reason: Specialized developmental function, not core ISR role.
- term:
id: GO:0030282
label: bone mineralization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 regulates osteoblast differentiation and bone formation.
action: KEEP_AS_NON_CORE
reason: Important physiological function but secondary to ISR role
(PMID:15109498).
supported_by:
- reference_id: PMID:15109498
supporting_text: ATF4 is a substrate of RSK2 and an essential
regulator of osteoblast biology; implication for Coffin-Lowry
Syndrome.
- term:
id: GO:0030968
label: endoplasmic reticulum unfolded protein response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is a key effector of the PERK branch of the UPR during ER
stress.
action: ACCEPT
reason: Core function of ATF4 in the ISR/UPR (PMID:12871976,
PMID:33384352).
supported_by:
- reference_id: PMID:33384352
supporting_text: QRICH1 dictates the outcome of ER stress through
transcriptional control of proteostasis.
- term:
id: GO:0032590
label: dendrite membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Based on rat ortholog. Relates to GABA-B receptor interaction in
neurons.
action: KEEP_AS_NON_CORE
reason: Specialized neuronal localization.
- term:
id: GO:0032922
label: circadian regulation of gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 binds CRE elements in clock gene promoters.
action: KEEP_AS_NON_CORE
reason: Secondary function.
- term:
id: GO:0034198
label: cellular response to amino acid starvation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is translationally induced during amino acid deprivation via
GCN2-eIF2alpha pathway.
action: ACCEPT
reason: Core function - ATF4 is the central transcription factor activated
during amino acid starvation (PMID:11960987).
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- term:
id: GO:0034599
label: cellular response to oxidative stress
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: ATF4 regulates antioxidant gene expression in response to
oxidative stress.
action: ACCEPT
reason: ATF4 activates genes involved in redox homeostasis as part of the
ISR.
- term:
id: GO:0034976
label: response to endoplasmic reticulum stress
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is the key transcription factor downstream of PERK during ER
stress.
action: ACCEPT
reason: Core function (PMID:12871976, PMID:33384352).
- term:
id: GO:0035162
label: embryonic hemopoiesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Based on mouse knockout phenotype.
action: KEEP_AS_NON_CORE
reason: Developmental function, not core ISR role.
- term:
id: GO:0035497
label: cAMP response element binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 binds CRE sequences.
action: ACCEPT
reason: Core molecular function of ATF4 as a bZIP transcription factor.
- term:
id: GO:0036499
label: PERK-mediated unfolded protein response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is the key transcription factor downstream of PERK.
action: ACCEPT
reason: Core function (PMID:31023583, PMID:12871976).
supported_by:
- reference_id: PMID:31023583
supporting_text: 2019 Apr 22. ER and Nutrient Stress Promote Assembly
of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
- term:
id: GO:0042789
label: mRNA transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 regulates pol II transcription.
action: ACCEPT
reason: Core function.
- term:
id: GO:0043267
label: negative regulation of potassium ion transport
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Based on rat ortholog. Specialized neuronal function.
action: KEEP_AS_NON_CORE
reason: Specialized neuronal function.
- term:
id: GO:0043525
label: positive regulation of neuron apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 with CHOP can promote neuronal apoptosis during prolonged
stress.
action: KEEP_AS_NON_CORE
reason: Context-dependent pro-apoptotic function during chronic stress.
- term:
id: GO:0045667
label: regulation of osteoblast differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is required for osteoblast differentiation.
action: KEEP_AS_NON_CORE
reason: Important developmental function but not core ISR role
(PMID:15109498).
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 activates transcription of stress-responsive genes.
action: ACCEPT
reason: Core function.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 activates pol II-mediated transcription.
action: ACCEPT
reason: Core function.
- term:
id: GO:0046982
label: protein heterodimerization activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 heterodimerizes with other bZIP transcription factors via
its leucine zipper domain.
action: ACCEPT
reason: Core molecular function for DNA binding (PMID:12871976,
PMID:18940792).
supported_by:
- reference_id: PMID:18940792
supporting_text: 2008 Oct 21. C/EBP homology protein (CHOP) interacts
with activating transcription factor 4 (ATF4) and negatively
regulates the stress-dependent induction of the asparagine
synthetase gene.
- term:
id: GO:0048167
label: regulation of synaptic plasticity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 acts as a memory suppressor in neurons.
action: KEEP_AS_NON_CORE
reason: Specialized neuronal function.
- term:
id: GO:0070059
label: intrinsic apoptotic signaling pathway in response to endoplasmic
reticulum stress
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 with CHOP activates pro-apoptotic genes during prolonged ER
stress.
action: KEEP_AS_NON_CORE
reason: Context-dependent function during chronic stress, not the primary
adaptive role.
- term:
id: GO:0070309
label: lens fiber cell morphogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Based on mouse knockout phenotype.
action: KEEP_AS_NON_CORE
reason: Developmental function.
- term:
id: GO:0071456
label: cellular response to hypoxia
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is stabilized under hypoxia via reduced hydroxylation by
PHD3.
action: ACCEPT
reason: ATF4 is regulated by hypoxia and contributes to hypoxic gene
expression.
- term:
id: GO:0090575
label: RNA polymerase II transcription regulator complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 forms transcription factor complexes.
action: ACCEPT
reason: ATF4 forms heterodimeric complexes with other bZIP factors.
- term:
id: GO:0120163
label: negative regulation of cold-induced thermogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 suppresses thermogenic gene expression.
action: KEEP_AS_NON_CORE
reason: Specialized metabolic function.
- term:
id: GO:0140296
label: general transcription initiation factor binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 interacts with general transcription machinery.
action: ACCEPT
reason: Consistent with its function as a transcription factor.
- term:
id: GO:0140297
label: DNA-binding transcription factor binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 interacts with other transcription factors.
action: ACCEPT
reason: ATF4 heterodimerizes with other bZIP transcription factors.
- term:
id: GO:0140467
label: integrated stress response signaling
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is THE central transcription factor of the ISR.
action: ACCEPT
reason: Core function - ATF4 is the master transcription factor effector
of the ISR (PMID:32132707).
supported_by:
- reference_id: PMID:32132707
supporting_text: Mar 4. Mitochondrial stress is relayed to the cytosol
by an OMA1-DELE1-HRI pathway.
- term:
id: GO:1903377
label: negative regulation of oxidative stress-induced neuron intrinsic
apoptotic signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 can be protective against oxidative stress in neurons.
action: KEEP_AS_NON_CORE
reason: Context-dependent neuroprotective function.
- term:
id: GO:1990253
label: cellular response to leucine starvation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 is induced by leucine starvation via GCN2.
action: ACCEPT
reason: Core function - amino acid sensing is a primary trigger of ATF4
induction.
- term:
id: GO:1990589
label: ATF4-CREB1 transcription factor complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate of IBA annotation.
action: ACCEPT
reason: ATF4-CREB1 complex formation is documented.
- term:
id: GO:1990590
label: ATF1-ATF4 transcription factor complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate of IBA annotation.
action: ACCEPT
reason: ATF4-ATF1 complex formation is documented.
- term:
id: GO:1990737
label: response to manganese-induced endoplasmic reticulum stress
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Specific stressor that activates ER stress and ATF4.
action: KEEP_AS_NON_CORE
reason: Specific toxic stressor response.
- term:
id: GO:1990841
label: promoter-specific chromatin binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF4 binds to specific promoter sequences.
action: ACCEPT
reason: Core molecular function.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: Nucleoplasmic localization confirmed by immunofluorescence.
action: ACCEPT
reason: Consistent with nuclear transcription factor function.
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:12871976
review:
summary: Nuclear localization discussed in study.
action: ACCEPT
reason: Consistent with transcription factor function.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:20102225
review:
summary: Nuclear localization in bZIP interaction study.
action: ACCEPT
reason: Consistent with transcription factor function.
supported_by:
- reference_id: PMID:20102225
supporting_text: Identification of bZIP interaction partners of viral
proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:23661758
review:
summary: Nuclear localization in bZIP network study.
action: ACCEPT
reason: Consistent with transcription factor function.
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions
diversified over a billion years of evolution.
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:28186491
review:
summary: Nuclear localization discussed.
action: ACCEPT
reason: Consistent with transcription factor function.
supported_by:
- reference_id: PMID:28186491
supporting_text: Combinatorial bZIP dimers display complex DNA-binding
specificity landscapes.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:20102225
review:
summary: Transcriptional regulation discussed.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:20102225
supporting_text: Identification of bZIP interaction partners of viral
proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:23661758
review:
summary: Transcriptional regulation discussed.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions
diversified over a billion years of evolution.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:28186491
review:
summary: Transcriptional regulation discussed.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:28186491
supporting_text: Combinatorial bZIP dimers display complex DNA-binding
specificity landscapes.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:16343488
review:
summary: ATF4 with Zhangfei cooperatively activates CRE-driven
transcription.
action: ACCEPT
reason: Direct experimental evidence for transcriptional activation.
supported_by:
- reference_id: PMID:16343488
supporting_text: 2005 Dec 6. Cooperative interaction of Zhangfei and
ATF4 in transactivation of the cyclic AMP response element.
- term:
id: GO:0140467
label: integrated stress response signaling
evidence_type: NAS
original_reference_id: PMID:28566324
review:
summary: ATF4 as key regulator of mitochondrial stress response.
action: ACCEPT
reason: Core function in ISR.
supported_by:
- reference_id: PMID:28566324
supporting_text: 2017 May 31. Multi-omics analysis identifies ATF4 as
a key regulator of the mitochondrial stress response in mammals.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:31023583
review:
summary: ATF4 transcription factor activity demonstrated in PERK-eIF2alpha
axis study.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:31023583
supporting_text: 2019 Apr 22. ER and Nutrient Stress Promote Assembly
of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
- term:
id: GO:0036499
label: PERK-mediated unfolded protein response
evidence_type: IDA
original_reference_id: PMID:31023583
review:
summary: ATF4 mediates PERK-dependent transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:31023583
supporting_text: 2019 Apr 22. ER and Nutrient Stress Promote Assembly
of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:23123191
review:
summary: ATF4 transcription factor activity demonstrated, regulated by CK2
phosphorylation.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:23123191
supporting_text: Functional interaction of protein kinase CK2 and
activating transcription factor 4 (ATF4), a key player in the
cellular stress response.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:32132707
review:
summary: ATF4 transcription factor activity in mitochondrial stress
response.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:32132707
supporting_text: Mar 4. Mitochondrial stress is relayed to the cytosol
by an OMA1-DELE1-HRI pathway.
- term:
id: GO:0140468
label: HRI-mediated signaling
evidence_type: IDA
original_reference_id: PMID:32132706
review:
summary: ATF4 is downstream of HRI in mitochondrial stress signaling.
action: ACCEPT
reason: Core function - ATF4 is activated by HRI during mitochondrial
stress via DELE1.
supported_by:
- reference_id: PMID:32132706
supporting_text: Mar 4. A pathway coordinated by DELE1 relays
mitochondrial stress to the cytosol.
- term:
id: GO:0034599
label: cellular response to oxidative stress
evidence_type: IMP
original_reference_id: PMID:23392669
review:
summary: ATF4 mediates transcriptional response to oxidative stress in
neurons.
action: ACCEPT
reason: Core function in stress response.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0034976
label: response to endoplasmic reticulum stress
evidence_type: IDA
original_reference_id: PMID:12871976
review:
summary: ATF4 activates GRP78/BiP promoter during ER stress.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0034976
label: response to endoplasmic reticulum stress
evidence_type: IMP
original_reference_id: PMID:21113145
review:
summary: ATF4 transcriptionally regulates parkin during ER stress.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:21113145
supporting_text: 'Nov 26. Parkin is transcriptionally regulated by ATF4:
evidence for an interconnection between mitochondrial stress and ER stress.'
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:12871976
review:
summary: ATF4 activates GRP78/BiP transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:21113145
review:
summary: ATF4 activates parkin transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:21113145
supporting_text: 'Nov 26. Parkin is transcriptionally regulated by ATF4:
evidence for an interconnection between mitochondrial stress and ER stress.'
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: ISS
original_reference_id: PMID:23392669
review:
summary: Based on rat ortholog study of neuroprotection.
action: ACCEPT
reason: Consistent with core function.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:24939851
review:
summary: ATF4 activates DR5 transcription during ER stress.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:24939851
supporting_text: 2014 Jun 17. Role of activating transcription factor
3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization
of p53-deficient human colon cancer cells to tumor necrosis factor
(TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis
through up-regulation of death receptor 5 (DR5) by zerumbone and
celecoxib.
- term:
id: GO:0034599
label: cellular response to oxidative stress
evidence_type: IMP
original_reference_id: PMID:21113145
review:
summary: ATF4 mediates oxidative stress response.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:21113145
supporting_text: 'Nov 26. Parkin is transcriptionally regulated by ATF4:
evidence for an interconnection between mitochondrial stress and ER stress.'
- term:
id: GO:1903377
label: negative regulation of oxidative stress-induced neuron intrinsic
apoptotic signaling pathway
evidence_type: IGI
original_reference_id: PMID:23392669
review:
summary: ATF4 protects neurons against oxidative stress-induced apoptosis.
action: KEEP_AS_NON_CORE
reason: Specialized neuroprotective function.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: TAS
original_reference_id: PMID:14685163
review:
summary: Review discusses ATF4 transcriptional activation with CHOP.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:14685163
supporting_text: Roles of CHOP/GADD153 in endoplasmic reticulum
stress.
- term:
id: GO:1990253
label: cellular response to leucine starvation
evidence_type: IDA
original_reference_id: PMID:17267404
review:
summary: ATF4 binds chromatin during amino acid starvation.
action: ACCEPT
reason: Core function in amino acid sensing.
supported_by:
- reference_id: PMID:17267404
supporting_text: ATF2 is required for amino acid-regulated
transcription by orchestrating specific histone acetylation.
- term:
id: GO:1990841
label: promoter-specific chromatin binding
evidence_type: IDA
original_reference_id: PMID:17267404
review:
summary: ATF4 chromatin binding demonstrated by ChIP.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:17267404
supporting_text: ATF2 is required for amino acid-regulated
transcription by orchestrating specific histone acetylation.
- term:
id: GO:0034976
label: response to endoplasmic reticulum stress
evidence_type: IDA
original_reference_id: PMID:33384352
review:
summary: ATF4 cooperates with QRICH1 in ER stress response.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:33384352
supporting_text: QRICH1 dictates the outcome of ER stress through
transcriptional control of proteostasis.
- term:
id: GO:0140467
label: integrated stress response signaling
evidence_type: IDA
original_reference_id: PMID:32132707
review:
summary: ATF4 is the key effector of the ISR.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:32132707
supporting_text: Mar 4. Mitochondrial stress is relayed to the cytosol
by an OMA1-DELE1-HRI pathway.
- term:
id: GO:0140468
label: HRI-mediated signaling
evidence_type: IDA
original_reference_id: PMID:32132707
review:
summary: ATF4 downstream of HRI in mitochondrial stress.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:32132707
supporting_text: Mar 4. Mitochondrial stress is relayed to the cytosol
by an OMA1-DELE1-HRI pathway.
- term:
id: GO:1990837
label: sequence-specific double-stranded DNA binding
evidence_type: IDA
original_reference_id: PMID:28473536
review:
summary: ATF4 DNA binding specificity characterized, including methylation
sensitivity.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:28473536
supporting_text: Impact of cytosine methylation on DNA binding
specificities of human transcription factors.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 can repress transcription in certain contexts.
action: KEEP_AS_NON_CORE
reason: ATF4 primarily activates transcription; repression is
context-dependent.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:11960987
review:
summary: ATF4 transcription factor activity in nutrient sensing.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:15109498
review:
summary: ATF4 transcription factor activity in osteoblast differentiation.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:15109498
supporting_text: ATF4 is a substrate of RSK2 and an essential
regulator of osteoblast biology; implication for Coffin-Lowry
Syndrome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23123191
review:
summary: ATF4 interacts with CK2 as a substrate.
action: MODIFY
reason: This is a kinase-substrate interaction.
proposed_replacement_terms:
- id: GO:0019901
label: protein kinase binding
supported_by:
- reference_id: PMID:23123191
supporting_text: Functional interaction of protein kinase CK2 and
activating transcription factor 4 (ATF4), a key player in the
cellular stress response.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:23123191
review:
summary: Nuclear localization of ATF4-CK2 interaction.
action: ACCEPT
reason: Core localization.
supported_by:
- reference_id: PMID:23123191
supporting_text: Functional interaction of protein kinase CK2 and
activating transcription factor 4 (ATF4), a key player in the
cellular stress response.
- term:
id: GO:0008140
label: cAMP response element binding protein binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 interacts with CREB family members.
action: ACCEPT
reason: Documented interaction.
- term:
id: GO:0030282
label: bone mineralization
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 regulates bone mineralization via osteoblast function.
action: KEEP_AS_NON_CORE
reason: Physiological function but not core ISR role.
- term:
id: GO:0030968
label: endoplasmic reticulum unfolded protein response
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 is a key UPR effector.
action: ACCEPT
reason: Core function.
- term:
id: GO:0031667
label: response to nutrient levels
evidence_type: IDA
original_reference_id: PMID:11960987
review:
summary: ATF4 mediates transcriptional response to nutrient deprivation.
action: ACCEPT
reason: Core function in nutrient sensing.
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- term:
id: GO:0034599
label: cellular response to oxidative stress
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 mediates oxidative stress response.
action: ACCEPT
reason: Core function.
- term:
id: GO:0035162
label: embryonic hemopoiesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Based on mouse knockout phenotype.
action: KEEP_AS_NON_CORE
reason: Developmental function.
- term:
id: GO:0036499
label: PERK-mediated unfolded protein response
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 downstream of PERK.
action: ACCEPT
reason: Core function.
- term:
id: GO:0045667
label: regulation of osteoblast differentiation
evidence_type: IDA
original_reference_id: PMID:15109498
review:
summary: ATF4 is required for osteoblast differentiation.
action: KEEP_AS_NON_CORE
reason: Important but not core ISR function.
supported_by:
- reference_id: PMID:15109498
supporting_text: ATF4 is a substrate of RSK2 and an essential
regulator of osteoblast biology; implication for Coffin-Lowry
Syndrome.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:11960987
review:
summary: ATF4 activates ASNS transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:15109498
review:
summary: ATF4 activates osteoblast gene transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:15109498
supporting_text: ATF4 is a substrate of RSK2 and an essential
regulator of osteoblast biology; implication for Coffin-Lowry
Syndrome.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:23123191
review:
summary: ATF4 transcriptional activity regulated by CK2.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:23123191
supporting_text: Functional interaction of protein kinase CK2 and
activating transcription factor 4 (ATF4), a key player in the
cellular stress response.
- term:
id: GO:0046982
label: protein heterodimerization activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 heterodimerizes with bZIP partners.
action: ACCEPT
reason: Core molecular function.
- term:
id: GO:0048167
label: regulation of synaptic plasticity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 regulates memory-related genes.
action: KEEP_AS_NON_CORE
reason: Specialized neuronal function.
- term:
id: GO:0070309
label: lens fiber cell morphogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Based on mouse knockout phenotype.
action: KEEP_AS_NON_CORE
reason: Developmental function.
- term:
id: GO:0070982
label: L-asparagine metabolic process
evidence_type: IDA
original_reference_id: PMID:11960987
review:
summary: ATF4 activates asparagine synthetase (ASNS) gene transcription.
action: ACCEPT
reason: Core target gene regulation.
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IMP
original_reference_id: PMID:16445384
review:
summary: ATF4 regulates SNAT2 expression.
action: ACCEPT
reason: Core function in amino acid transporter regulation.
supported_by:
- reference_id: PMID:16445384
supporting_text: Characterization of the amino acid response element
within the human sodium-coupled neutral amino acid transporter 2
(SNAT2) System A transporter gene.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IDA
original_reference_id: PMID:15911876
review:
summary: ATF4 DNA binding activity demonstrated.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:15911876
supporting_text: FIAT represses ATF4-mediated transcription to
regulate bone mass in transgenic mice.
- term:
id: GO:0000785
label: chromatin
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: ATF4 binds chromatin as a transcription factor.
action: ACCEPT
reason: Consistent with transcription factor function.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase
II-specific
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: ATF4 is a pol II transcription factor.
action: ACCEPT
reason: Core molecular function.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase
II-specific
evidence_type: IDA
original_reference_id: PMID:12871976
review:
summary: ATF4 transcription factor activity demonstrated.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0120163
label: negative regulation of cold-induced thermogenesis
evidence_type: ISS
original_reference_id: PMID:22980225
review:
summary: ATF4 suppresses thermogenic gene expression.
action: KEEP_AS_NON_CORE
reason: Specialized metabolic function.
supported_by:
- reference_id: PMID:22980225
supporting_text: 2012 Sep 11. Effects of ATF4 on PGC1α expression in
brown adipose tissue and metabolic responses to cold stress.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA
binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 binds CRE sequences.
action: ACCEPT
reason: Core molecular function.
- term:
id: GO:0005813
label: centrosome
evidence_type: IDA
original_reference_id: PMID:20873783
review:
summary: ATF4 localizes to centrosome with NEK6.
action: KEEP_AS_NON_CORE
reason: Non-canonical localization, not central to ISR function.
supported_by:
- reference_id: PMID:20873783
supporting_text: Oct 22. Characterization of hNek6 interactome reveals
an important role for its short N-terminal domain and colocalization
with proteins at the centrosome.
- term:
id: GO:0019901
label: protein kinase binding
evidence_type: IPI
original_reference_id: PMID:20873783
review:
summary: ATF4 interacts with NEK6 kinase.
action: ACCEPT
reason: Documented kinase interaction.
supported_by:
- reference_id: PMID:20873783
supporting_text: Oct 22. Characterization of hNek6 interactome reveals
an important role for its short N-terminal domain and colocalization
with proteins at the centrosome.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:20873783
review:
summary: ATF4 forms protein complexes.
action: ACCEPT
reason: Consistent with bZIP dimerization.
supported_by:
- reference_id: PMID:20873783
supporting_text: Oct 22. Characterization of hNek6 interactome reveals
an important role for its short N-terminal domain and colocalization
with proteins at the centrosome.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9796061
review:
summary: ATF4 is synthesized in the cytosol.
action: ACCEPT
reason: ATF4 is translated in the cytoplasm.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:23392669
review:
summary: Nuclear localization in Parkinson's disease model.
action: ACCEPT
reason: Core localization.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0032057
label: negative regulation of translational initiation in response to
stress
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 is part of the translation regulation pathway via ISR.
action: KEEP_AS_NON_CORE
reason: ATF4 is a consequence of translation regulation, not a direct
regulator of translation initiation.
- term:
id: GO:0034644
label: cellular response to UV
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 is induced by UV stress.
action: ACCEPT
reason: Part of general stress response.
- term:
id: GO:0034198
label: cellular response to amino acid starvation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 is induced by amino acid starvation.
action: ACCEPT
reason: Core function.
- term:
id: GO:0042789
label: mRNA transcription by RNA polymerase II
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 regulates pol II transcription.
action: ACCEPT
reason: Core function.
- term:
id: GO:0036499
label: PERK-mediated unfolded protein response
evidence_type: TAS
original_reference_id: PMID:22934019
review:
summary: ATF4 downstream of PERK discussed in review.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:22934019
supporting_text: The endoplasmic reticulum stress response in aging
and age-related diseases.
- term:
id: GO:0034976
label: response to endoplasmic reticulum stress
evidence_type: IMP
original_reference_id: PMID:24939851
review:
summary: ATF4 mediates ER stress response.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:24939851
supporting_text: 2014 Jun 17. Role of activating transcription factor
3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization
of p53-deficient human colon cancer cells to tumor necrosis factor
(TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis
through up-regulation of death receptor 5 (DR5) by zerumbone and
celecoxib.
- term:
id: GO:0036499
label: PERK-mediated unfolded protein response
evidence_type: TAS
original_reference_id: PMID:22013210
review:
summary: ATF4 downstream of PERK in UPR.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:22013210
supporting_text: 'The unfolded protein response: integrating stress signals
through the stress sensor IRE1α.'
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase
II-specific
evidence_type: IDA
original_reference_id: PMID:11478948
review:
summary: ATF4 transcription factor activity with CHOP.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:11478948
supporting_text: The cAMP response element binding protein-2 (CREB-2)
can interact with the C/EBP-homologous protein (CHOP).
- term:
id: GO:0043522
label: leucine zipper domain binding
evidence_type: IDA
original_reference_id: PMID:11478948
review:
summary: ATF4 interacts with CHOP via leucine zipper.
action: ACCEPT
reason: Core molecular function for bZIP heterodimerization.
supported_by:
- reference_id: PMID:11478948
supporting_text: The cAMP response element binding protein-2 (CREB-2)
can interact with the C/EBP-homologous protein (CHOP).
- term:
id: GO:0061629
label: RNA polymerase II-specific DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:11478948
review:
summary: ATF4 interacts with CHOP transcription factor.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:11478948
supporting_text: The cAMP response element binding protein-2 (CREB-2)
can interact with the C/EBP-homologous protein (CHOP).
- term:
id: GO:1990617
label: CHOP-ATF4 complex
evidence_type: IDA
original_reference_id: PMID:11478948
review:
summary: ATF4-CHOP complex formation demonstrated.
action: ACCEPT
reason: Important transcription factor complex in stress response.
supported_by:
- reference_id: PMID:11478948
supporting_text: The cAMP response element binding protein-2 (CREB-2)
can interact with the C/EBP-homologous protein (CHOP).
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:11478948
review:
summary: Nuclear localization with CHOP.
action: ACCEPT
reason: Core localization.
supported_by:
- reference_id: PMID:11478948
supporting_text: The cAMP response element binding protein-2 (CREB-2)
can interact with the C/EBP-homologous protein (CHOP).
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:11478948
review:
summary: ATF4-CHOP activates transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:11478948
supporting_text: The cAMP response element binding protein-2 (CREB-2)
can interact with the C/EBP-homologous protein (CHOP).
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:15775988
review:
summary: ATF4-CHOP activates TRB3 transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:15775988
supporting_text: Mar 10. TRB3, a novel ER stress-inducible gene, is
induced via ATF4-CHOP pathway and is involved in cell death.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:18940792
review:
summary: ATF4 activates transcription, regulated by CHOP.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:18940792
supporting_text: 2008 Oct 21. C/EBP homology protein (CHOP) interacts
with activating transcription factor 4 (ATF4) and negatively
regulates the stress-dependent induction of the asparagine
synthetase gene.
- term:
id: GO:1990617
label: CHOP-ATF4 complex
evidence_type: NAS
original_reference_id: PMID:15775988
review:
summary: ATF4-CHOP complex discussed.
action: ACCEPT
reason: Important complex.
supported_by:
- reference_id: PMID:15775988
supporting_text: Mar 10. TRB3, a novel ER stress-inducible gene, is
induced via ATF4-CHOP pathway and is involved in cell death.
- term:
id: GO:1990617
label: CHOP-ATF4 complex
evidence_type: IPI
original_reference_id: PMID:18940792
review:
summary: ATF4-CHOP interaction demonstrated.
action: ACCEPT
reason: Important complex.
supported_by:
- reference_id: PMID:18940792
supporting_text: 2008 Oct 21. C/EBP homology protein (CHOP) interacts
with activating transcription factor 4 (ATF4) and negatively
regulates the stress-dependent induction of the asparagine
synthetase gene.
- term:
id: GO:1990589
label: ATF4-CREB1 transcription factor complex
evidence_type: IDA
original_reference_id: PMID:12871976
review:
summary: ATF4-CREB1 complex demonstrated.
action: ACCEPT
reason: Core transcription factor complex.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:1990590
label: ATF1-ATF4 transcription factor complex
evidence_type: IDA
original_reference_id: PMID:12871976
review:
summary: ATF4-ATF1 complex demonstrated.
action: ACCEPT
reason: Core transcription factor complex.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IDA
original_reference_id: PMID:12871976
review:
summary: ATF4 binds to ATF/CRE regulatory sequences.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:12871976
supporting_text: '2003 Jul 18. Induction of Grp78/BiP by translational block:
activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE
site independent of the endoplasmic reticulum stress elements.'
- term:
id: GO:0010575
label: positive regulation of vascular endothelial growth factor
production
evidence_type: IMP
original_reference_id: PMID:22915762
review:
summary: ATF4 induces VEGF during ER stress.
action: KEEP_AS_NON_CORE
reason: Context-dependent angiogenic function.
supported_by:
- reference_id: PMID:22915762
supporting_text: Epub 2012 Aug 20. The unfolded protein response
induces the angiogenic switch in human tumor cells through the
PERK/ATF4 pathway.
- term:
id: GO:0042149
label: cellular response to glucose starvation
evidence_type: IMP
original_reference_id: PMID:22915762
review:
summary: ATF4 mediates glucose starvation response.
action: ACCEPT
reason: Part of nutrient stress response.
supported_by:
- reference_id: PMID:22915762
supporting_text: Epub 2012 Aug 20. The unfolded protein response
induces the angiogenic switch in human tumor cells through the
PERK/ATF4 pathway.
- term:
id: GO:0043565
label: sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:22915762
review:
summary: ATF4 DNA binding activity.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:22915762
supporting_text: Epub 2012 Aug 20. The unfolded protein response
induces the angiogenic switch in human tumor cells through the
PERK/ATF4 pathway.
- term:
id: GO:0045943
label: positive regulation of transcription by RNA polymerase I
evidence_type: IMP
original_reference_id: PMID:22915762
review:
summary: ATF4 may regulate pol I transcription.
action: UNDECIDED
reason: ATF4 is primarily a pol II transcription factor. Pol I regulation
is atypical and needs verification.
supported_by:
- reference_id: PMID:22915762
supporting_text: Epub 2012 Aug 20. The unfolded protein response
induces the angiogenic switch in human tumor cells through the
PERK/ATF4 pathway.
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IDA
original_reference_id: PMID:21113145
review:
summary: ATF4 binds parkin promoter.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:21113145
supporting_text: 'Nov 26. Parkin is transcriptionally regulated by ATF4:
evidence for an interconnection between mitochondrial stress and ER stress.'
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: TAS
original_reference_id: PMID:23392669
review:
summary: ATF4 cis-regulatory binding discussed.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:23392669
review:
summary: Cytoplasmic ATF4 in neurons.
action: ACCEPT
reason: ATF4 can be cytoplasmic before stress-induced nuclear
translocation.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0034399
label: nuclear periphery
evidence_type: IDA
original_reference_id: PMID:23392669
review:
summary: ATF4 at nuclear periphery in neurons.
action: KEEP_AS_NON_CORE
reason: Specialized neuronal localization.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0043005
label: neuron projection
evidence_type: IDA
original_reference_id: PMID:23392669
review:
summary: ATF4 in neuron projections.
action: KEEP_AS_NON_CORE
reason: Specialized neuronal localization.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0043065
label: positive regulation of apoptotic process
evidence_type: TAS
original_reference_id: PMID:23392669
review:
summary: ATF4 can promote apoptosis during stress.
action: KEEP_AS_NON_CORE
reason: Context-dependent pro-apoptotic function.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:1990037
label: Lewy body core
evidence_type: IDA
original_reference_id: PMID:23392669
review:
summary: ATF4 found in Lewy bodies in Parkinson's disease.
action: KEEP_AS_NON_CORE
reason: Pathological localization in neurodegeneration.
supported_by:
- reference_id: PMID:23392669
supporting_text: ATF4 protects against neuronal death in cellular
Parkinson's disease models by maintaining levels of parkin.
- term:
id: GO:0032922
label: circadian regulation of gene expression
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 regulates circadian genes.
action: KEEP_AS_NON_CORE
reason: Secondary function.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9635804
review:
summary: ATF4 nucleoplasmic localization in Reactome pathway.
action: ACCEPT
reason: Core localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9635892
review:
summary: ATF4 nucleoplasmic localization.
action: ACCEPT
reason: Core localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9635936
review:
summary: ATF4 nucleoplasmic localization.
action: ACCEPT
reason: Core localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9653893
review:
summary: ATF4 nucleoplasmic localization.
action: ACCEPT
reason: Core localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9761815
review:
summary: ATF4 nucleoplasmic localization.
action: ACCEPT
reason: Core localization.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IDA
original_reference_id: PMID:18940792
review:
summary: ATF4 DNA binding demonstrated.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:18940792
supporting_text: 2008 Oct 21. C/EBP homology protein (CHOP) interacts
with activating transcription factor 4 (ATF4) and negatively
regulates the stress-dependent induction of the asparagine
synthetase gene.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18940792
review:
summary: ATF4 interacts with CHOP.
action: MODIFY
reason: This is a specific bZIP-bZIP interaction.
proposed_replacement_terms:
- id: GO:0043522
label: leucine zipper domain binding
supported_by:
- reference_id: PMID:18940792
supporting_text: 2008 Oct 21. C/EBP homology protein (CHOP) interacts
with activating transcription factor 4 (ATF4) and negatively
regulates the stress-dependent induction of the asparagine
synthetase gene.
- term:
id: GO:0043525
label: positive regulation of neuron apoptotic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4-CHOP can promote neuronal apoptosis.
action: KEEP_AS_NON_CORE
reason: Context-dependent, not core function.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:18940792
review:
summary: ATF4 activates transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:18940792
supporting_text: 2008 Oct 21. C/EBP homology protein (CHOP) interacts
with activating transcription factor 4 (ATF4) and negatively
regulates the stress-dependent induction of the asparagine
synthetase gene.
- term:
id: GO:0070059
label: intrinsic apoptotic signaling pathway in response to endoplasmic
reticulum stress
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4-CHOP activate apoptotic pathway during prolonged ER stress.
action: KEEP_AS_NON_CORE
reason: Context-dependent, chronic stress response.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:15775988
review:
summary: ATF4-CHOP activate TRB3 transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:15775988
supporting_text: Mar 10. TRB3, a novel ER stress-inducible gene, is
induced via ATF4-CHOP pathway and is involved in cell death.
- term:
id: GO:0034976
label: response to endoplasmic reticulum stress
evidence_type: IDA
original_reference_id: PMID:19061639
review:
summary: ATF4 in ER stress response.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:19061639
supporting_text: Role of SERCA1 truncated isoform in the proapoptotic
calcium transfer from ER to mitochondria during ER stress.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16682973
review:
summary: ATF4 interacts with CEP290/nephrocystin-6.
action: ACCEPT
reason: Functionally relevant interaction affecting ATF4 activity.
supported_by:
- reference_id: PMID:16682973
supporting_text: The centrosomal protein nephrocystin-6 is mutated in
Joubert syndrome and activates transcription factor ATF4.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:16682973
review:
summary: Nuclear localization with CEP290.
action: ACCEPT
reason: Core localization.
supported_by:
- reference_id: PMID:16682973
supporting_text: The centrosomal protein nephrocystin-6 is mutated in
Joubert syndrome and activates transcription factor ATF4.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15677469
review:
summary: ATF4 interacts with mitosin/CENP-F.
action: KEEP_AS_NON_CORE
reason: Interaction affecting ATF4 regulation but not core function.
supported_by:
- reference_id: PMID:15677469
supporting_text: 2005 Jan 26. Mitosin/CENP-F as a negative regulator
of activating transcription factor-4.
- term:
id: GO:0003677
label: DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 DNA binding.
action: ACCEPT
reason: Core molecular function.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IDA
original_reference_id: PMID:15788408
review:
summary: ATF4 DNA binding in arsenite response.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:15788408
supporting_text: 2005 Mar 23. The oxidative stressor arsenite
activates vascular endothelial growth factor mRNA transcription by
an ATF4-dependent mechanism.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: TAS
original_reference_id: PMID:12689582
review:
summary: Review of ATF4 as transcription factor.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:12689582
supporting_text: All roads lead to ATF4.
- term:
id: GO:0005634
label: nucleus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Nuclear localization.
action: ACCEPT
reason: Core localization.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Cytoplasmic localization.
action: ACCEPT
reason: ATF4 is translated in cytoplasm.
- term:
id: GO:0006094
label: gluconeogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 regulates gluconeogenic genes.
action: KEEP_AS_NON_CORE
reason: Metabolic function, not core ISR role.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 regulates transcription.
action: ACCEPT
reason: Core function.
- term:
id: GO:0006366
label: transcription by RNA polymerase II
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 in pol II transcription.
action: ACCEPT
reason: Core function.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 activates transcription.
action: ACCEPT
reason: Core function.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IMP
original_reference_id: PMID:11960987
review:
summary: ATF4 activates ASNS transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:11960987
supporting_text: 2002 Apr 17. ATF4 is a mediator of the
nutrient-sensing response pathway that activates the human
asparagine synthetase gene.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: NAS
original_reference_id: PMID:9190894
review:
summary: ATF4 with HTLV-1 Tax in transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:9190894
supporting_text: Functional interaction of the HTLV-1 transactivator
Tax with activating transcription factor-4 (ATF4).
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ATF4 activates pol II transcription.
action: ACCEPT
reason: Core function.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:15788408
review:
summary: ATF4 activates VEGF transcription.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:15788408
supporting_text: 2005 Mar 23. The oxidative stressor arsenite
activates vascular endothelial growth factor mRNA transcription by
an ATF4-dependent mechanism.
core_functions:
- molecular_function:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
description: ATF4 is a bZIP transcription factor that serves as the central
effector of the Integrated Stress Response (ISR). ATF4 binds to cAMP
response elements (CRE) and C/EBP-ATF response elements (CARE/AARE) as
homo- or heterodimers to activate transcription of stress-responsive
genes. Key targets include amino acid metabolism genes (ASNS, PSAT1,
PHGDH), amino acid transporters (SLC7A11/xCT, SLC1A5), autophagy genes
(MAP1LC3B, BECN1, ATG5, ATG7, ATG12), ER chaperones (GRP78/BiP), and
transcription factors (CHOP/DDIT3, ATF3). ATF4 translation is uniquely
controlled by upstream open reading frames (uORFs) that enable
preferential translation when eIF2alpha is phosphorylated by
stress-sensing kinases (PERK, GCN2, PKR, HRI). ATF4 also cooperates with
NRF2 as an obligatory metabolic activator of the antioxidant response
(PMID:37410595). Neill and Masson (PMID:36825279) catalogued 41
well-validated ATF4 target genes.
- molecular_function:
id: GO:0046982
label: protein heterodimerization activity
description: ATF4 forms heterodimers with other bZIP transcription factors
via its leucine zipper domain, including CHOP/DDIT3, C/EBP family members
(CEBPB, CEBPG), CREB1, ATF1, ATF3, and other bZIP partners. The choice of
dimerization partner determines target gene specificity and whether the
outcome is adaptive or pro-apoptotic. Neill and Masson (PMID:36825279)
catalogued 14 direct dimerization partners for ATF4.
proposed_new_terms: []
suggested_questions:
- question: What determines whether ATF4 promotes cell survival (adaptive ISR)
versus cell death (terminal UPR/apoptosis)?
- question: How do different bZIP dimerization partners affect ATF4 target
gene specificity?
- question: What is the significance of ATF4 localization to the centrosome
and its interaction with NEK6?
suggested_experiments:
- description: ChIP-seq comparing ATF4 chromatin binding with different stress
conditions (ER stress vs amino acid starvation vs mitochondrial stress) to
define stress-specific target genes
hypothesis: Different stressors activate distinct ATF4 target gene programs
- description: Time-course proteomics following ATF4 induction to distinguish
early adaptive targets from late pro-apoptotic targets
hypothesis: Temporal dynamics of ATF4 activity determines cell fate
- description: CRISPR screens to identify ATF4-dependent genes essential for
survival during different stress conditions
hypothesis: Specific ATF4 target genes are required for stress adaptation
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with
GO terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data
to orthologs by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
Location vocabulary mapping
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation
data to orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000113
title: Gene Ontology annotation of human sequence-specific DNA binding
transcription factors based on the TFClass database
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning
models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:11238952
title: ATF4 degradation relies on a phosphorylation-dependent interaction
with the SCF(betaTrCP) ubiquitin ligase.
findings:
- statement: ATF4 is ubiquitinated by SCF(BTRC) for proteasomal
degradation
- id: PMID:11478948
title: The cAMP response element binding protein-2 (CREB-2) can interact
with the C/EBP-homologous protein (CHOP).
findings:
- statement: ATF4 interacts with CHOP via leucine zipper domain
- id: PMID:11960987
title: ATF4 is a mediator of the nutrient-sensing response pathway that
activates the human asparagine synthetase gene.
findings:
- statement: ATF4 binds NSRE-1 sequence and activates ASNS transcription
in response to amino acid or glucose deprivation
- id: PMID:12689582
title: All roads lead to ATF4.
findings:
- statement: Review of ATF4 function as stress-responsive transcription
factor
- id: PMID:12743605
title: SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in
human tumors and is regulated by hypoxia.
findings: []
- id: PMID:12812986
title: 'DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein
that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction
with mutation.'
findings: []
- id: PMID:12860379
title: Functional interaction of the subunit 3 of RNA polymerase II (RPB3)
with transcription factor-4 (ATF4).
findings: []
- id: PMID:12871976
title: 'Induction of Grp78/BiP by translational block: activation of the Grp78
promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic
reticulum stress elements.'
findings:
- statement: ATF4 activates GRP78/BiP promoter via ATF/CRE sequence
- statement: ATF4 forms complexes with ATF1 and CREB1
- id: PMID:14685163
title: Roles of CHOP/GADD153 in endoplasmic reticulum stress.
findings: []
- id: PMID:15109498
title: ATF4 is a substrate of RSK2 and an essential regulator of osteoblast
biology.
findings:
- statement: ATF4 is phosphorylated by RSK2 at Ser-245
- statement: ATF4 is required for osteoblast differentiation
- id: PMID:15677469
title: Mitosin/CENP-F as a negative regulator of activating transcription
factor-4.
findings: []
- id: PMID:15775988
title: TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP
pathway and is involved in cell death.
findings: []
- id: PMID:15788408
title: The oxidative stressor arsenite activates vascular endothelial growth
factor mRNA transcription by an ATF4-dependent mechanism.
findings: []
- id: PMID:15911876
title: FIAT represses ATF4-mediated transcription to regulate bone mass in
transgenic mice.
findings: []
- id: PMID:16169070
title: 'A human protein-protein interaction network: a resource for annotating
the proteome.'
findings: []
- id: PMID:16189514
title: Towards a proteome-scale map of the human protein-protein interaction
network.
findings: []
- id: PMID:16219772
title: p300 modulates ATF4 stability and transcriptional activity
independently of its acetyltransferase domain.
findings: []
- id: PMID:16343488
title: Cooperative interaction of Zhangfei and ATF4 in transactivation of
the cyclic AMP response element.
findings: []
- id: PMID:16445384
title: Characterization of the amino acid response element within the human
sodium-coupled neutral amino acid transporter 2 (SNAT2) System A
transporter gene.
findings: []
- id: PMID:16682973
title: The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome
and activates transcription factor ATF4.
findings: []
- id: PMID:17267404
title: ATF2 is required for amino acid-regulated transcription by
orchestrating specific histone acetylation.
findings: []
- id: PMID:18330356
title: Construction and characterization of a normalized yeast two-hybrid
library derived from a human protein-coding clone collection.
findings: []
- id: PMID:18940792
title: C/EBP homology protein (CHOP) interacts with activating transcription
factor 4 (ATF4) and negatively regulates the stress-dependent induction of
the asparagine synthetase gene.
findings:
- statement: CHOP is an ATF4 binding partner
- statement: CHOP suppresses ATF4-dependent ASNS induction
- id: PMID:19061639
title: Role of SERCA1 truncated isoform in the proapoptotic calcium transfer
from ER to mitochondria during ER stress.
findings: []
- id: PMID:19164757
title: ERAD inhibitors integrate ER stress with an epigenetic mechanism to
activate BH3-only protein NOXA in cancer cells.
findings: []
- id: PMID:19447967
title: Shifted Transversal Design smart-pooling for high coverage
interactome mapping.
findings: []
- id: PMID:20102225
title: Identification of bZIP interaction partners of viral proteins HBZ,
MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
findings: []
- id: PMID:20211142
title: An atlas of combinatorial transcriptional regulation in mouse and
man.
findings: []
- id: PMID:20873783
title: Characterization of hNek6 interactome reveals an important role for
its short N-terminal domain and colocalization with proteins at the
centrosome.
findings: []
- id: PMID:20936779
title: A human MAP kinase interactome.
findings: []
- id: PMID:21113145
title: 'Parkin is transcriptionally regulated by ATF4: evidence for an interconnection
between mitochondrial stress and ER stress.'
findings: []
- id: PMID:21408167
title: 'New modularity of DAP-kinases: alternative splicing of the DRP-1 gene
produces a ZIPk-like isoform.'
findings: []
- id: PMID:21988832
title: Toward an understanding of the protein interaction network of the
human liver.
findings: []
- id: PMID:22013210
title: "The unfolded protein response: integrating stress signals through the
stress sensor IRE1α."
findings: []
- id: PMID:22915762
title: The unfolded protein response induces the angiogenic switch in human
tumor cells through the PERK/ATF4 pathway.
findings: []
- id: PMID:22934019
title: The endoplasmic reticulum stress response in aging and age-related
diseases.
findings: []
- id: PMID:22980225
title: "Effects of ATF4 on PGC1α expression in brown adipose tissue and metabolic
responses to cold stress."
findings: []
- id: PMID:23123191
title: Functional interaction of protein kinase CK2 and activating
transcription factor 4 (ATF4), a key player in the cellular stress
response.
findings:
- statement: ATF4 is phosphorylated by CK2 at Ser-215
- statement: CK2 phosphorylation regulates ATF4 stability and activity
- id: PMID:23392669
title: ATF4 protects against neuronal death in cellular Parkinson's disease
models by maintaining levels of parkin.
findings: []
- id: PMID:23661758
title: Networks of bZIP protein-protein interactions diversified over a
billion years of evolution.
findings: []
- id: PMID:24939851
title: Role of activating transcription factor 3 (ATF3) in endoplasmic
reticulum (ER) stress-induced sensitization of p53-deficient human colon
cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing
ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor
5 (DR5) by zerumbone and celecoxib.
findings: []
- id: PMID:25241761
title: Using an in situ proximity ligation assay to systematically profile
endogenous protein-protein interactions in a pathway network.
findings: []
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:25910212
title: Widespread macromolecular interaction perturbations in human genetic
disorders.
findings: []
- id: PMID:26700459
title: Involvement of Nrf2 in proteasome inhibition-mediated induction of
ORP150 in thyroid cancer cells.
findings: []
- id: PMID:26871637
title: Widespread Expansion of Protein Interaction Capabilities by
Alternative Splicing.
findings: []
- id: PMID:27107014
title: An inter-species protein-protein interaction network across vast
evolutionary distance.
findings: []
- id: PMID:28186491
title: Combinatorial bZIP dimers display complex DNA-binding specificity
landscapes.
findings: []
- id: PMID:28473536
title: Impact of cytosine methylation on DNA binding specificities of human
transcription factors.
findings: []
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and
disease networks.
findings: []
- id: PMID:28566324
title: Multi-omics analysis identifies ATF4 as a key regulator of the
mitochondrial stress response in mammals.
findings: []
- id: PMID:29892012
title: An interactome perturbation framework prioritizes damaging missense
mutations for developmental disorders.
findings: []
- id: PMID:31023583
title: "ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes
through the PERK-eIF2α Axis."
findings: []
- id: PMID:31413325
title: HENA, heterogeneous network-based data set for Alzheimer's disease.
findings: []
- id: PMID:31515488
title: Extensive disruption of protein interactions by genetic variants
across the allele frequency spectrum in human populations.
findings: []
- id: PMID:32132706
title: A pathway coordinated by DELE1 relays mitochondrial stress to the
cytosol.
findings:
- statement: OMA1-DELE1-HRI pathway transmits mitochondrial stress to
activate ATF4
- id: PMID:32132707
title: Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI
pathway.
findings:
- statement: ATF4 is activated downstream of HRI during mitochondrial
stress
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease
Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
findings: []
- id: PMID:32911434
title: A functionally defined high-density NRF2 interactome reveals new
conditional regulators of ARE transactivation.
findings: []
- id: PMID:33384352
title: QRICH1 dictates the outcome of ER stress through transcriptional
control of proteostasis.
findings:
- statement: QRICH1 cooperates with ATF4 in ER stress response
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the
human interactome.
findings: []
- id: PMID:9190894
title: Functional interaction of the HTLV-1 transactivator Tax with
activating transcription factor-4 (ATF4).
findings: []
- id: PMID:9488481
title: ZIP kinase, a novel serine/threonine kinase which mediates apoptosis.
findings: []
- id: Reactome:R-HSA-9635804
title: Reactome pathway involving ATF4.
findings: []
- id: Reactome:R-HSA-9635892
title: Reactome pathway involving ATF4.
findings: []
- id: Reactome:R-HSA-9635936
title: Reactome pathway involving ATF4.
findings: []
- id: Reactome:R-HSA-9653893
title: Reactome pathway involving ATF4.
findings: []
- id: Reactome:R-HSA-9761815
title: Reactome pathway involving ATF4.
findings: []
- id: Reactome:R-HSA-9796061
title: Reactome pathway involving ATF4.
findings: []
- id: file:human/ATF4/ATF4-deep-research-cyberian.md
title: Deep research review of ATF4 function (Cyberian provider)
findings:
- statement: ATF4 is the central effector of the Integrated Stress
Response (ISR)
- statement: ATF4 translation is controlled by upstream open reading
frames (uORFs) that enable preferential translation under stress when
eIF2alpha is phosphorylated
- statement: ATF4 regulates target genes through heterodimerization with
partners including CHOP, C/EBP family members, and JUN
- statement: ATF4 regulates autophagy genes including MAP1LC3B, BECN1,
ATG5, ATG7, ATG12
- statement: ATF4 is an obligatory metabolic activator of NRF2
- statement: ATF4's role in lens development - knockout mice show
microphthalmia due to p53-mediated apoptosis
- statement: ATF4 is essential for osteoblast differentiation and bone
formation, phosphorylated by RSK2
- statement: ATF4 functions as a memory suppressor in neurons, localizes
to dendrites and is transported to nucleus via importins
- id: PMID:36825279
title: 'A stay of execution: ATF4 regulation and potential outcomes for the integrated
stress response'
findings:
- statement: Catalogued 41 well-validated ATF4 target genes
- statement: Identified 14 direct dimerization partners for ATF4
- statement: Documented 33 post-translational modifications affecting ATF4
- id: PMID:27629041
title: The integrated stress response
findings:
- statement: ATF4 is described as the main effector of the ISR
- statement: ISR is activated by four eIF2alpha kinases (PERK, GCN2, PKR,
HRI)
- id: PMID:1534408
title: Molecular cloning of human CREB-2
findings:
- statement: Original cloning of ATF4/CREB-2 from Jurkat T-cells
- statement: ATF4 was initially characterized as a transcriptional
repressor of CRE-dependent transcription
- id: PMID:27358398
title: Upstream Open Reading Frames Differentially Regulate Gene-specific
Translation in the Integrated Stress Response
findings:
- statement: Detailed mechanism of uORF-mediated translational control of
ATF4
- id: PMID:26960794
title: Transcription factor ATF4 directs basal and stress-induced gene
expression in the unfolded protein response and cholesterol metabolism in
the liver
findings:
- statement: ATF4 affects only ~7.5% of stress-regulated genes in liver vs
~50% for PERK
- statement: In liver, CHOP expression occurs independently of ATF4, with
ATF6 as major contributor
- statement: ATF4 deletion results in altered cholesterol homeostasis
- id: PMID:20514020
title: Regulation of autophagy by ATF4 in response to severe hypoxia
findings:
- statement: ATF4 directly regulates autophagy genes through CRE sites
- statement: ATF4 facilitates autophagy through direct binding to LC3B
promoter
- id: PMID:22095285
title: Mutation of ATF4 mediates resistance of neuronal cell lines against
oxidative stress by inducing xCT expression
findings:
- statement: ATF4 induces xCT/SLC7A11 for cystine import and glutathione
biosynthesis
- id: PMID:11018027
title: Crystal structure of the CCAAT box/enhancer binding protein beta
activating transcription factor-4 basic leucine zipper heterodimer
findings:
- statement: C/EBPbeta-ATF4 heterodimer forms asymmetric coiled-coil
structure
- statement: Basic region of ATF4 forms continuous alpha-helix even
without DNA
- id: PMID:37410595
title: The integrated stress response effector ATF4 is an obligatory
metabolic activator of NRF2
findings:
- statement: ATF4 increases NRF2 transcription
- statement: ATF4 induces CHAC1 (glutathione-degrading enzyme) important
for NRF2 activation
- id: PMID:22585903
title: The transcription factor network associated with the amino acid
response in mammalian cells
findings:
- statement: ATF4 binding to AARE occurs within 30-60 minutes of amino
acid deprivation
- id: PMID:27211800
title: The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor
Progression During Endoplasmic Reticulum Stress.
findings:
- statement: Review of PERK-ATF4-CHOP pathway in cancer
- id: PMID:29230213
title: Transcription Factor C/EBP Homologous Protein in Health and Diseases.
findings:
- statement: CHOP triggers intrinsic apoptotic pathway through BCL-2
inhibition and BIM upregulation
- statement: CHOP activates extrinsic pathway through DR5 induction
- id: PMID:18957537
title: Importin-mediated retrograde transport of CREB2 from distal processes
to the nucleus in neurons.
findings:
- statement: ATF4/CREB2 localizes to distal dendrites
- statement: ATF4 binds importins alpha1 and alpha6 for nuclear transport
- id: PMID:16153175
title: Translational regulation of GCN4 and the general amino acid control
of yeast
findings:
- statement: GCN4 is the yeast functional homolog of mammalian ATF4
- statement: GCN4 regulates >500 genes including amino acid biosynthetic
enzymes
- id: PMID:12925279
title: Inducible enhancement of memory storage and synaptic plasticity in
transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP
proteins
findings:
- statement: ATF4 inhibition enhances hippocampal-based spatial memory
- statement: ATF4 inhibition enhances long-term potentiation (LTP)
- id: PMID:29432178
title: General amino acid control in fission yeast is regulated by a
nonconserved transcription factor with functions analogous to Gcn4/Atf4
findings:
- statement: In fission yeast, Fil1 (GATA-type TF) mediates amino acid
starvation response analogous to ATF4/GCN4
aliases:
- CREB2
- CREB-2
- TAXREB67
tags:
- ferroptosis