ATF-6 is an ER membrane-bound bZIP transcription factor that functions as one of the three canonical branches of the endoplasmic reticulum unfolded protein response (UPRER) in C. elegans. Under ER stress, ATF-6 dissociates from BiP, traffics to the Golgi, undergoes regulated intramembrane proteolysis (S1P/S2P cleavage), and the released N-terminal fragment translocates to the nucleus where it activates transcription of ER proteostasis genes. ATF-6 cooperates with the IRE-1/XBP-1 branch and is synthetically lethal with ire-1/xbp-1 or pek-1 deletion, causing L2 larval arrest. Beyond classical UPR functions, ATF-6 regulates ER calcium homeostasis through calreticulin (crt-1) expression, influencing ER-mitochondrial calcium signaling and lifespan. ATF-6 loss extends lifespan by approximately 43-57% through altered ER-mitochondrial calcium flux.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030968 endoplasmic reticulum unfolded protein response | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-6 is a well-established component of the ER UPR in C. elegans. ATF-6 functions as one of three canonical branches of the UPRER alongside IRE-1/XBP-1 and PEK-1 (PMID:16184190, file:worm/atf-6/atf-6-deep-research-falcon.md). Upon ER stress, ATF-6 activates transcription of genes involved in the UPR, particularly constitutive UPR (c-UPR) genes important during development. Reason: This IBA annotation is well-supported by direct experimental evidence. Shen et al. (2005) demonstrated that atf-6 is required for expression of many c-UPR genes, and acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1 (PMID:16184190). Multiple subsequent studies confirm ATF-6's role in UPR signaling. Supporting Evidence: PMID:16184190 deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2 file:worm/atf-6/atf-6-deep-research-falcon.md The UPRER has three branches: IRE-1/xbp-1, PERK/pek-1, and ATF-6/atf-6 |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-6 localizes to the nucleus after activation. Upon ER stress, ATF-6 is cleaved to release an N-terminal bZIP transcription factor that translocates to the nucleus to activate target gene transcription (UniProt Q20435, file:worm/atf-6/atf-6-deep-research-falcon.md). Reason: As a bZIP transcription factor, ATF-6 must localize to the nucleus to carry out its transcriptional regulatory function. The cleaved N-terminal fragment (ATF-6n) contains the bZIP DNA-binding domain and translocates to the nucleus. This is consistent with mammalian ATF6 function and supported by phylogenetic inference. Supporting Evidence: UniProt:Q20435 SUBCELLULAR LOCATION: Nucleus |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-6 is a bZIP transcription factor that regulates transcription of UPR target genes. Microarray analysis showed that atf-6 regulates many constitutive UPR (c-UPR) genes and some inducible UPR (i-UPR) genes (PMID:16184190). Reason: The IBA annotation is well-supported. ATF-6 contains a bZIP domain characteristic of transcription factors and has been experimentally shown to regulate transcription of UPR genes in C. elegans. This is a core molecular function of the protein. Supporting Evidence: PMID:16184190 C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-6 contains a bZIP domain (aa 250-299) that mediates sequence-specific DNA binding. The basic motif (aa 252-275) and leucine zipper (aa 281-295) are characteristic of bZIP transcription factors that bind specific cis-regulatory sequences (UniProt Q20435). Reason: This IBA annotation is supported by domain analysis and phylogenetic inference. ATF-6 contains a well-characterized bZIP domain that enables DNA binding to specific regulatory sequences such as ER stress response elements (ERSE). Supporting Evidence: UniProt:Q20435 Belongs to the bZIP family. ATF subfamily |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-6 functions as a sequence-specific DNA-binding transcription factor. Upon activation by ER stress and proteolytic cleavage, the N-terminal fragment translocates to the nucleus and activates transcription of target genes (PMID:16184190, UniProt Q20435). Reason: This IBA annotation accurately captures the core molecular function of ATF-6 as a transcription factor. ATF-6 belongs to the bZIP family ATF subfamily and has been experimentally shown to regulate transcription of UPR genes. Supporting Evidence: PMID:16184190 C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis UniProt:Q20435 Belongs to the bZIP family. ATF subfamily |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: ATF-6 contains a bZIP domain that mediates DNA binding. This IEA annotation is based on UniProt keyword mapping and is consistent with the protein's function as a transcription factor. Reason: This is a valid but general annotation. The more specific annotation to GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding) is more informative, but this annotation is not incorrect. Supporting Evidence: UniProt:Q20435 Belongs to the bZIP family. ATF subfamily |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: ATF-6 is a DNA-binding transcription factor. This IEA annotation from InterPro is accurate and supported by experimental evidence showing ATF-6 regulates transcription of UPR genes. Reason: The IEA annotation is correct. ATF-6 belongs to the bZIP family and has been experimentally demonstrated to regulate transcription of target genes in C. elegans. Supporting Evidence: PMID:16184190 C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: This is a duplicate annotation to the IBA annotation above. ATF-6 localizes to the nucleus after activation and proteolytic cleavage. Reason: This IEA annotation is correct and consistent with the IBA annotation. The nuclear localization is essential for ATF-6's transcription factor function. Duplicate annotations with different evidence codes are acceptable. Supporting Evidence: UniProt:Q20435 SUBCELLULAR LOCATION: Nucleus |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: ATF-6 is involved in DNA-templated transcription as a bZIP transcription factor that activates transcription of UPR target genes. Reason: This is a valid but general annotation. ATF-6's role in transcription is well-established through its function as a UPR transcription factor. Supporting Evidence: UniProt:Q20435 Transcription factor (By similarity) |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: ATF-6 regulates DNA-templated transcription of UPR target genes. This IEA annotation from InterPro is consistent with the known function of ATF-6. Reason: This annotation is correct and supported by experimental evidence showing ATF-6 regulates transcription of UPR genes. Supporting Evidence: PMID:16184190 C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: ATF-6 is an ER membrane-bound transcription factor with a single-pass transmembrane domain (aa 324-344). Under unstressed conditions, ATF-6 resides in the ER membrane (UniProt Q20435). Reason: While membrane localization is correct, this annotation is too general. ATF-6 specifically localizes to the ER membrane where it resides until activation by ER stress. A more specific annotation to endoplasmic reticulum membrane would be more informative. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: UniProt:Q20435 Membrane {ECO:0000255}; Single-pass membrane protein {ECO:0000255} |
| GO:0036500 ATF6-mediated unfolded protein response | IMP PMID:20733002 Protein misfolding induces hypoxic preconditioning via a sub... | ACCEPT | Summary: This study by Mao & Crowder (2010) showed that pharmacological induction of misfolded proteins stimulates a protective response to hypoxic injury that requires ATF-6 along with IRE-1 and XBP-1, demonstrating ATF-6's role in the UPR pathway (PMID:20733002). Reason: This is a highly specific and accurate annotation. The study directly demonstrates ATF-6's involvement in the UPR response to protein misfolding. The term GO:0036500 specifically captures the ATF6 branch of the UPR. Supporting Evidence: PMID:20733002 pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6 |
| GO:0036500 ATF6-mediated unfolded protein response | IMP PMID:31570707 Constitutive XBP-1s-mediated activation of the endoplasmic r... | ACCEPT | Summary: Waldherr et al. (2019) demonstrated that atf-6 loss of function enhances tau toxicity in C. elegans tauopathy models. Furthermore, atf-6 loss abolishes the ability of neuronal XBP-1s overexpression to suppress tauopathy, indicating ATF-6 is required for XBP-1s-mediated UPRER protection (PMID:31570707). Reason: This is an excellent annotation supported by direct experimental evidence. The study shows that atf-6 loss of function worsens tauopathy phenotypes and is essential for XBP-1s-mediated protection, demonstrating ATF-6's role in the UPR pathway. Supporting Evidence: PMID:31570707 atf-6 loss of function in Tau (low) animals enhances mild behavioral defects observed in a liquid environment PMID:31570707 atf-6 loss of function abolishes the ability of neuronal overexpression of xbp-1s in Tau (high) animals to suppress severe behavioral defects |
| GO:0036500 ATF6-mediated unfolded protein response | IMP PMID:32905769 Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Ho... | ACCEPT | Summary: Burkewitz et al. (2020) demonstrated that ATF-6 functions in the ER UPR and regulates lifespan through ER-mitochondrial calcium homeostasis. While atf-6 mutants are not hypersensitive to canonical proteotoxic ER stress (tunicamycin), ATF-6 regulates calreticulin expression and ER calcium handling (file:worm/atf-6/atf-6-deep-research-falcon.md). Reason: This annotation is well-supported. The study provides detailed mechanistic insight into ATF-6's role in the UPR, showing it regulates ER proteostasis genes including calreticulin. Supporting Evidence: file:worm/atf-6/atf-6-deep-research-falcon.md atf-6 mutants are not hypersensitive to tunicamycin and show relatively modest transcriptomic changes (26 down, 101 up genes) compared to other UPR branches PMID:32905769 Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:16184190 Genetic interactions due to constitutive and inducible gene ... | ACCEPT | Summary: Shen et al. (2005) performed microarray analysis showing that ATF-6 is required for expression of many constitutive UPR (c-UPR) genes, demonstrating its role as a transcriptional activator (PMID:16184190). Reason: This annotation is well-supported by experimental evidence. ATF-6 functions as a transcriptional activator of UPR genes, consistent with its role as a bZIP transcription factor that activates gene expression upon ER stress. Supporting Evidence: PMID:16184190 C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:18216284 APY-1, a novel Caenorhabditis elegans apyrase involved in un... | ACCEPT | Summary: Uccelletti et al. (2008) showed that ER stress-induced transcription of apy-1 requires both ire-1 and atf-6, demonstrating ATF-6's role in positive regulation of transcription (PMID:18216284). Reason: This annotation provides additional evidence for ATF-6's role as a transcriptional activator. The study shows that ATF-6 is required for ER stress-induced transcription of the target gene apy-1. Supporting Evidence: PMID:18216284 This increase was not observed in C. elegans mutants defective in ire-1 or atf-6, demonstrating the requirement of both ER stress sensors for up-regulation of apy-1 |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:24068940 Integration of the unfolded protein and oxidative stress res... | ACCEPT | Summary: Glover-Cutter et al. (2013) demonstrated that SKN-1/Nrf binds to common downstream targets with XBP-1 and ATF-6, indicating ATF-6 binds to transcription regulatory regions (PMID:24068940). Reason: This IDA annotation is supported by experimental evidence. The study shows ATF-6 co-regulates target genes with other UPR transcription factors, consistent with its function as a sequence-specific DNA-binding transcription factor. Supporting Evidence: PMID:24068940 binds to common downstream targets with XBP-1 and ATF-6 |
| GO:0036500 ATF6-mediated unfolded protein response | IMP PMID:25298520 Developmental defects in a Caenorhabditis elegans model for ... | ACCEPT | Summary: Brokate-Llanos et al. (2014) found interactions between gale-1 and the unfolded protein response in a C. elegans model of type III galactosemia (PMID:25298520). The specific involvement of ATF-6 in this context requires verification. Reason: The annotation is consistent with ATF-6's established role in the UPR. While the abstract mentions general UPR interactions, ATF-6 is a canonical component of the UPR pathway and the GO term GO:0036500 specifically captures the ATF6 branch. Supporting Evidence: PMID:25298520 Interestingly, we found interactions between gale-1 and the unfolded protein response |
| GO:0035966 response to topologically incorrect protein | IMP PMID:23335331 A novel interaction between aging and ER overload in a prote... | ACCEPT | Summary: Schipanski et al. (2013) showed that downregulation of UPR pathways in the worm favors mutant SRP-2 (neuroserpin) accumulation, demonstrating the role of UPR components in responding to misfolded proteins (PMID:23335331). Reason: This annotation is appropriate. The study demonstrates that UPR pathways including ATF-6 are involved in the response to misfolded/aggregated proteins. The term GO:0035966 captures the response to topologically incorrect (misfolded) proteins. Supporting Evidence: PMID:23335331 downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation |
| GO:0008340 determination of adult lifespan | IMP PMID:32905769 Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Ho... | NEW | Summary: Burkewitz et al. (2020) demonstrated that atf-6 deletion extends median lifespan by 57% (ok551) or 43% (CRISPR null), with improved pharyngeal pumping during aging (file:worm/atf-6/atf-6-deep-research-falcon.md). This is noted in UniProt annotations for this gene. Reason: Strong experimental evidence from multiple alleles demonstrates ATF-6 regulates lifespan. This annotation appears in UniProt but was not in the GOA tsv file. Supporting Evidence: file:worm/atf-6/atf-6-deep-research-falcon.md atf-6(ok551) deletion increases median lifespan by 57% (p < 0.0001), and an independent CRISPR null increases lifespan by 43% (p < 0.0001) PMID:32905769 Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis. |
| GO:0032469 endoplasmic reticulum calcium ion homeostasis | IMP PMID:32905769 Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Ho... | NEW | Summary: Burkewitz et al. (2020) showed that atf-6 loss reprograms ER calcium handling by downregulating calreticulin/crt-1, enhancing ER-to-mitochondria Ca2+ transfer (file:worm/atf-6/atf-6-deep-research-falcon.md). This is noted in UniProt annotations. Reason: This annotation captures an important aspect of ATF-6 function beyond classical UPR. The study provides direct evidence that ATF-6 regulates ER calcium homeostasis through calreticulin expression. Supporting Evidence: file:worm/atf-6/atf-6-deep-research-falcon.md crt-1(bz29) null phenocopies atf-6 longevity (~38% lifespan extension vs WT), while reducing itr-1 function suppresses atf-6 longevity PMID:32905769 Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis. |
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Download this section (compressed HTML)Q: What are the direct transcriptional targets of ATF-6 in C. elegans? While microarray studies identified genes regulated by atf-6, direct ChIP-seq or CUT&RUN analysis would clarify which genes are directly bound by ATF-6 versus indirectly regulated.
Q: How does ATF-6 cooperate with XBP-1s at the molecular level? Studies show ATF-6 is required for XBP-1s-mediated protection in tauopathy models, but the mechanism of cooperation (heterodimerization, co-binding) is unclear in worms.
Experiment: ChIP-seq analysis of ATF-6 binding sites. Direct identification of ATF-6 genomic binding sites would clarify direct versus indirect target genes and reveal the DNA sequences recognized by C. elegans ATF-6.
Hypothesis: ATF-6 directly binds to ERSE elements in target gene promoters
Experiment: Tissue-specific rescue experiments to determine in which tissues ATF-6 acts to regulate lifespan. This would clarify whether the longevity phenotype is mediated through intestine, neurons, or other tissues.
Hypothesis: ATF-6 functions primarily in intestinal cells to regulate lifespan
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