EDF1

UniProt ID: O60869
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

EDF1 (Endothelial Differentiation-related Factor 1), also known as Multiprotein Bridging Factor 1 (MBF1), is a small (~16 kDa) evolutionarily conserved transcriptional coactivator. The protein acts as a molecular bridge between gene-specific transcription factors (including nuclear receptors NR5A1, NR1H3/LXRa, PPARg, and bZIP factors ATF1, ATF2, CREB1) and the TATA-binding protein (TBP) component of the general transcription machinery. EDF1 contains an N-terminal MBF1 domain with an IQ motif for calmodulin binding and a C-terminal helix-turn-helix (HTH) DNA-binding domain. Recent work has revealed a second major function: EDF1 is recruited to collided ribosomes where it coordinates ribosome-associated quality control (RQC) by recruiting the GIGYF2-eIF4E2 translational repressor complex, and it is required for robust activation of the GCN2-mediated integrated stress response (ISR). Cryo-EM analyses place EDF1 at a conserved binding site on the 40S subunit near the mRNA entry channel at the collision interface, and recruitment to collided ribosomes is ZNF598-independent but RACK1-dependent (PMID:32744497). EDF1 loss reduces ZNF598-mediated eS10/uS10 ubiquitylation and attenuates ZAKΞ±β†’p38 ribotoxic stress signalling, and in yeast/human cell fractionation experiments EDF1 is found exclusively in the cytoplasm with no detectable nuclear pool during ISR, supporting a primary cytoplasmic ribosome-associated role with context-dependent nuclear coactivator activity (PMID:39566505). In endothelial cells, cytoplasmic EDF1 sequesters calmodulin to regulate nitric oxide synthase activity. Subcellular localization is dynamic, with phosphorylation by PKA promoting nuclear accumulation.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005634 nucleus
IBA
GO_REF:0000033
ACCEPT
Summary: EDF1 localizes to both cytoplasm and nucleus, with nuclear localization enhanced by PKA-mediated phosphorylation or by co-expression with nuclear receptors like NR5A1 [PMID:10567391, PMID:15112053]. The IBA annotation is phylogenetically well-supported and consistent with experimental evidence.
Reason: Nuclear localization is experimentally validated. Studies show that "coexpression of the nuclear protein Ad4BP/SF-1 with hMBF1 induced accumulation of hMBF1 in the nucleus" [PMID:10567391] and PKA activation promotes nuclear accumulation [PMID:15112053].
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
file:human/EDF1/EDF1-deep-research-openai.md
GO:0003677 DNA binding
IEA
GO_REF:0000120
MODIFY
Summary: EDF1 contains a C-terminal Cro/C1-type helix-turn-helix domain (IPR001387), a known DNA-binding motif. However, experimental studies show that MBF1 does not directly bind DNA [PMID:8164657]. The HTH domain appears to function in ribosome binding rather than DNA binding.
Reason: The original MBF1 characterization paper explicitly states "Neither MBF1, MBF2, nor a combination of them binds to DNA" [PMID:8164657]. Although EDF1 has a DNA-binding domain fold, it functions as a bridging factor rather than a direct DNA binder. The HTH domain functions in ribosome binding during collision response.
Supporting Evidence:
PMID:8164657
Mediators of activation of fushi tarazu gene transcription by BmFTZ-F1.
GO:0005516 calmodulin binding
IEA
GO_REF:0000043
ACCEPT
Summary: EDF1 contains an IQ motif and experimentally binds calmodulin in a calcium- and phosphorylation- regulated manner [PMID:10816571, PMID:15112053]. This is a well-established core function.
Reason: Calmodulin binding is experimentally demonstrated. UniProt records that "Binding to calmodulin is regulated by calcium and phosphorylation of the IQ motif" based on PMID:10816571 and PMID:15112053. Multiple mutagenesis studies confirm specific residues involved in CALM binding.
Supporting Evidence:
GO:0005634 nucleus
IEA
GO_REF:0000044
ACCEPT
Summary: Duplicate of IBA annotation. IEA mapping from UniProt subcellular location vocabulary. Nuclear localization is well supported experimentally.
Reason: Nuclear localization is confirmed by multiple experimental studies showing EDF1 localizes to the nucleus upon activation by PKA or binding to nuclear receptors.
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0005737 cytoplasm
IEA
GO_REF:0000044
ACCEPT
Summary: EDF1 localizes to cytoplasm where it sequesters calmodulin. IEA from UniProt subcellular location vocabulary, supported by experimental evidence.
Reason: Cytoplasmic localization is experimentally validated, particularly in resting cells where EDF1 binds calmodulin. "While hMBF1 was detected in the cytoplasm by immunostaining" [PMID:10567391].
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0030154 cell differentiation
IEA
GO_REF:0000043
KEEP AS NON CORE
Summary: While EDF1 was named for its role in endothelial differentiation and affects differentiation phenotypes when knocked down, this term is very broad. The protein is involved in transcriptional regulation that affects differentiation rather than being a core differentiation factor.
Reason: EDF1 silencing affects endothelial cell organization into capillary networks (differentiation) [PMID:20185128], but this is a downstream consequence of its calmodulin-sequestering and transcriptional coactivator functions rather than a direct role in differentiation machinery.
Supporting Evidence:
GO:0005515 protein binding
IPI
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuc...
MODIFY
Summary: This IPI evidence from PMID:12040021 documents binding to nuclear receptors (NR5A2, NR1H3, PPARg) and the TFIID complex. The term "protein binding" is too generic; more specific terms exist for these interactions.
Reason: "protein binding" is uninformative for annotation purposes. The specific interactions documented are with nuclear receptors and transcription factor complexes, which have more specific GO terms. The coactivator function is already captured by GO:0003713.
Supporting Evidence:
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism.
GO:0005515 protein binding
IPI
PMID:21217774
RAC3 is a pro-migratory co-activator of ERΞ±.
REMOVE
Summary: PMID:21217774 is about RAC3 as an ERalpha coactivator. EDF1 appears in the phage display screen as an interactor (Supplemental Table 1), but this is a high-throughput study and EDF1 was not further characterized.
Reason: This paper focuses on RAC3, not EDF1. EDF1 was identified in a phage display screen but not validated or characterized. The "protein binding" term provides no functional insight.
Supporting Evidence:
PMID:21217774
RAC3 is a pro-migratory co-activator of ERΞ±.
GO:0005515 protein binding
IPI
PMID:24008843
Structure homology and interaction redundancy for discoverin...
REMOVE
Summary: PMID:24008843 describes computational prediction of virus-host interactions using structure homology. This is a high-throughput computational study, not experimental characterization of EDF1 interactions.
Reason: This paper describes computational predictions of virus-host interactions, not experimental evidence for EDF1 protein binding. The "protein binding" annotation provides no biological insight about EDF1 function.
Supporting Evidence:
PMID:24008843
Structure homology and interaction redundancy for discovering virus-host protein interactions.
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network.
REMOVE
Summary: PMID:25416956 is the HI-III human interactome map - a large-scale Y2H study. EDF1 interactions were identified in this systematic screen but the term "protein binding" is uninformative.
Reason: Large-scale interactome study providing no functional insight about specific EDF1 interactions. "protein binding" annotation without specifying binding partners is not informative for gene function annotation.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network.
GO:0005515 protein binding
IPI
PMID:31527615
The RNA-mediated estrogen receptor Ξ± interactome of hormone-...
REMOVE
Summary: PMID:31527615 examines the RNA-mediated estrogen receptor alpha interactome. EDF1 was identified in this proteomics study but the generic "protein binding" term provides no functional insight.
Reason: High-throughput proteomics study. Generic "protein binding" annotation is uninformative. If EDF1 specifically interacts with ESR1 in transcriptional regulation, more specific terms should be used.
Supporting Evidence:
PMID:31527615
The RNA-mediated estrogen receptor Ξ± interactome of hormone-dependent human breast cancer cell nuclei.
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ...
REMOVE
Summary: PMID:32814053 maps interactomes of neurodegenerative disease proteins including Huntingtin. EDF1 was identified as an HTT interactor in this proteomics study.
Reason: High-throughput interactome study. While EDF1-HTT interaction is documented, the generic "protein binding" term is uninformative. The biological relevance of this interaction is not characterized.
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:35156780
CFTR interactome mapping using the mammalian membrane two-hy...
REMOVE
Summary: PMID:35156780 studies CFTR interactome using membrane two-hybrid screening. EDF1 was identified as a CFTR interactor.
Reason: High-throughput CFTR interactome study. The relevance of EDF1-CFTR interaction is unclear and not characterized. Generic "protein binding" is uninformative.
Supporting Evidence:
PMID:35156780
CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system.
GO:0005515 protein binding
IPI
PMID:36012204
Differential CFTR-Interactome Proximity Labeling Procedures ...
REMOVE
Summary: PMID:36012204 uses proximity labeling to identify CFTR interactors. EDF1 was enriched in this proteomics study.
Reason: High-throughput proximity labeling study for CFTR. Generic "protein binding" annotation is uninformative. The biological significance of EDF1 in CFTR interactome is not established.
Supporting Evidence:
PMID:36012204
Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters.
GO:0005654 nucleoplasm
IDA
GO_REF:0000052
ACCEPT
Summary: Nucleoplasm localization based on immunofluorescence data from Human Protein Atlas. Consistent with known nuclear localization of EDF1 when functioning as transcriptional coactivator.
Reason: EDF1 functions as a transcriptional coactivator in the nucleus, consistent with nucleoplasm localization. IDA evidence from immunofluorescence is appropriate.
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0005829 cytosol
IDA
GO_REF:0000052
ACCEPT
Summary: Cytosol localization from Human Protein Atlas immunofluorescence. Consistent with EDF1's cytosolic role in calmodulin sequestration and ribosome quality control. Independent biochemical fractionation (PMID:39566505) reports EDF1 as exclusively cytoplasmic during ISR, and ribosome-collision recruitment (PMID:32744497) is a cytoplasmic event.
Reason: EDF1 has well-documented cytosolic functions including calmodulin binding and ribosome collision response. Cytosol localization is experimentally validated.
Supporting Evidence:
PMID:10567391
While hMBF1 was detected in the cytoplasm by immunostaining, coexpression of the nuclear protein Ad4BP/SF-1 with hMBF1 induced accumulation of hMBF1 in the nucleus
PMID:39566505
Interestingly, we observed that EDF1 exclusively resides in the cytoplasm, with no significant EDF1 signal detected in the nuclear fraction (Figure 6E).
file:human/EDF1/EDF1-deep-research-falcon.md
human EDF1 "exclusively resides in the cytoplasm" and that this does not change with stress in their tested conditions
GO:0001094 TFIID-class transcription factor complex binding
IDA
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuc...
ACCEPT
Summary: EDF1 directly binds TBP (a core TFIID component) and the TFIID complex to mediate transcriptional coactivation. This is a core molecular function of MBF1 proteins.
Reason: Direct binding to TFIID complex is central to EDF1's coactivator function. "MBF-1 interacts in vitro with the transcription factor IID complex" and "MBF-1 seems therefore to act as a bridging factor enabling interactions of nuclear receptors with the transcription machinery" [PMID:12040021].
Supporting Evidence:
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism.
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0003723 RNA binding
HDA
PMID:22658674
Insights into RNA biology from an atlas of mammalian mRNA-bi...
ACCEPT
Summary: PMID:22658674 is the Castello et al. mRNA interactome capture study that identified ~860 RNA-binding proteins in HeLa cells. EDF1 was identified as an RNA-binding protein. This is consistent with EDF1's role in ribosome collision response where it interacts with mRNA and ribosomes.
Reason: RNA binding is consistent with EDF1's established role at collided ribosomes where it interacts with mRNA at the ribosome collision interface. Recent cryo-EM structures show EDF1 occupying the mRNA entry channel of the 40S subunit (PMID:32744497).
Supporting Evidence:
PMID:22658674
May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
PMID:32744497
Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface.
file:human/EDF1/EDF1-deep-research-falcon.md
EDF1 also engages h18 and contacts uS3 near the mRNA entry channel
GO:0003723 RNA binding
HDA
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on ...
ACCEPT
Summary: PMID:22681889 (Baltz et al.) is another mRNA-bound proteome study identifying ~800 mRNA-binding proteins. EDF1 was identified in this independent screen, corroborating RNA binding function.
Reason: Independent confirmation of RNA binding from proteome-wide mRNA-bound protein identification. Consistent with EDF1's ribosome-associated functions.
Supporting Evidence:
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
GO:0005634 nucleus
NAS
PMID:8164657
Mediators of activation of fushi tarazu gene transcription b...
ACCEPT
Summary: PMID:8164657 is the original MBF1 characterization in silkworm. While this paper establishes MBF1 function, it does not directly demonstrate human EDF1 nuclear localization. Other references provide direct evidence.
Reason: Although PMID:8164657 is about silkworm MBF1, nuclear localization of human EDF1 is well established by other studies. The NAS evidence code indicates the reviewer traced evidence to this paper describing the conserved bridging function.
Supporting Evidence:
PMID:8164657
Mediators of activation of fushi tarazu gene transcription by BmFTZ-F1.
GO:0006355 regulation of DNA-templated transcription
TAS
PMID:8164657
Mediators of activation of fushi tarazu gene transcription b...
ACCEPT
Summary: MBF1/EDF1 regulates transcription by bridging transcription factors to TBP. This is the core function established in the original characterization paper.
Reason: Transcriptional regulation is the defining function of MBF1 proteins. "MBF1 and MBF2 form a bridge between BmFTZ-F1 and TBP and mediate transactivation" [PMID:8164657]. This function is conserved in human EDF1.
Supporting Evidence:
PMID:8164657
Mediators of activation of fushi tarazu gene transcription by BmFTZ-F1.
GO:0045893 positive regulation of DNA-templated transcription
TAS
PMID:8164657
Mediators of activation of fushi tarazu gene transcription b...
ACCEPT
Summary: EDF1/MBF1 functions as a transcriptional coactivator, positively regulating transcription of target genes. This is more specific than generic regulation.
Reason: MBF1 proteins mediate transcriptional activation, not repression. "MBF1 and MBF2 mediate activation of in vitro transcription from the fushi tarazu promoter by BmFTZ-F1" [PMID:8164657].
Supporting Evidence:
PMID:8164657
Mediators of activation of fushi tarazu gene transcription by BmFTZ-F1.
GO:0043388 positive regulation of DNA binding
IDA
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
ACCEPT
Summary: EDF1 enhances DNA-binding activity of transcription factors like ATF1 and NR5A1. This is consistent with its coactivator function.
Reason: "hMBF1 enhanced the DNA-binding activity of Ad4BP/SF-1" and similar effects on ATF family transcription factors are documented in PMID:10567391.
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0003713 transcription coactivator activity
IMP
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
ACCEPT
Summary: Transcription coactivator activity is the defining molecular function of EDF1. Demonstrated through multiple reporter assays showing enhancement of transcription factor activity.
Reason: Core molecular function. "hMBF1 mediated Ad4BP/SF-1-dependent transcriptional activation" and "hMBF1 also bound to ATF1, a member of the basic leucine zipper protein family, and mediated its activity as a transcriptional activator" [PMID:10567391].
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0005515 protein binding
IPI
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
MODIFY
Summary: PMID:10567391 documents binding to TBP, NR5A1, FOS, JUN, and ATF1. These are characterized interactions central to EDF1 function, but "protein binding" is too generic.
Reason: The specific interactions documented (TBP, nuclear receptors, bZIP transcription factors) have more informative GO terms. Generic "protein binding" should be replaced with specific molecular function terms.
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0005634 nucleus
IDA
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
ACCEPT
Summary: IDA evidence for nuclear localization from PMID:10567391, showing nuclear accumulation upon coexpression with NR5A1.
Reason: Direct experimental demonstration of nuclear localization under activating conditions.
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0005737 cytoplasm
IDA
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
ACCEPT
Summary: IDA evidence for cytoplasmic localization from immunostaining in PMID:10567391.
Reason: Direct experimental demonstration of cytoplasmic localization.
Supporting Evidence:
PMID:10567391
The role of human MBF1 as a transcriptional coactivator.
GO:0003713 transcription coactivator activity
IMP
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuc...
ACCEPT
Summary: Transcription coactivator activity demonstrated for nuclear receptors involved in lipid metabolism (NR1H3/LXRa, PPARg, NR5A2/LRH-1).
Reason: Core molecular function. "MBF-1 enhances the transcriptional activity of several nonsteroid nuclear receptors that are implicated in lipid metabolism" [PMID:12040021].
Supporting Evidence:
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism.
GO:0006355 regulation of DNA-templated transcription
TAS
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuc...
ACCEPT
Summary: General transcriptional regulation term appropriate for EDF1's coactivator function.
Reason: EDF1 regulates transcription by nuclear receptors including NR1H3, PPARg, NR5A2.
Supporting Evidence:
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism.
GO:0019216 regulation of lipid metabolic process
TAS
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuc...
KEEP AS NON CORE
Summary: EDF1 coactivates nuclear receptors (NR1H3/LXRa, PPARg) that regulate lipid metabolism genes. This is a downstream consequence of its coactivator function rather than a direct role in lipid metabolism.
Reason: While EDF1 enhances transcription by lipid metabolism-regulating nuclear receptors, this is an indirect effect through its coactivator function. It is not a lipid metabolism enzyme or direct regulator.
Supporting Evidence:
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism.
GO:0045446 endothelial cell differentiation
TAS
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuc...
KEEP AS NON CORE
Summary: EDF1 was named for its original identification in the context of endothelial differentiation. Its knockdown affects endothelial cell organization into capillary-like networks.
Reason: While EDF1 affects endothelial differentiation phenotypes, this is a downstream consequence of its calmodulin-sequestering and transcriptional coactivator functions rather than a direct role in differentiation machinery. The deep research notes "EDF1 appears to restrain full endothelial differentiation."
Supporting Evidence:
PMID:12040021
Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism.
GO:0006515 protein quality control for misfolded or incompletely synthesized proteins
IMP
PMID:32744497
EDF1 coordinates cellular responses to ribosome collisions.
NEW
Summary: NEW annotation for EDF1's ribosome-surveillance role. EDF1 is recruited to collided ribosomes, where it recruits the GIGYF2-eIF4E2 translational repressor complex and suppresses further initiation on defective mRNAs, placing it in ribosome-associated quality control rather than bulk cytoplasmic translation. Sinha et al. 2020 (PMID:32744497) provide direct biochemical/cryo-EM evidence; Kim et al. 2024 (PMID:39566505) extend the role to integrated stress response activation on collided ribosomes.
Reason: The PN-linked RQC suggestion stands up biologically and is more defensible than broad translation/cytoplasmic translation additions. EDF1 functions as a collision sensor and translational quality-control factor for stalled or damaged messages.
Supporting Evidence:
PMID:32744497
EDF1 recruits the translational repressors GIGYF2 and EIF4E2 to collided ribosomes to initiate a negative-feedback loop that prevents new ribosomes from translating defective mRNAs.
PMID:32744497
EDF1 functions upstream of ribosomal stall recognition as its depletion decreases ZNF598-mediated ubiquitylation of eS10 and uS10.
file:human/EDF1/EDF1-deep-research-falcon.md
EDF1 functions as an early collision-associated factor ("sensor/adaptor") that binds a conserved site on the 40S subunit near the mRNA entry channel at or near the collision interface and then helps coordinate downstream responses
file:human/EDF1/EDF1-deep-research-openai.md
In other words, EDF1 helps shut down translation initiation on messages that are broken or stalled, which is part of a process called No-Go Decay/Ribosome Quality Control (RQC).
GO:0043024 ribosomal small subunit binding
IDA
PMID:32744497
EDF1 coordinates cellular responses to ribosome collisions.
NEW
Summary: NEW annotation. Cryo-EM analysis demonstrates EDF1 binds a conserved site on the 40S ribosomal subunit at the mRNA entry channel, contacting rRNA helices h16/h18/h33 and ribosomal proteins uS3/uS4/eS30. Recruitment is RACK1-dependent and ZNF598-independent.
Reason: Direct cryo-EM structural evidence of EDF1 binding the 40S subunit is the primary mechanistic anchor for its ribosome-collision quality control role; this MF term is more informative than generic protein/RNA binding.
Supporting Evidence:
PMID:32744497
Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface.
file:human/EDF1/EDF1-deep-research-falcon.md
EDF1's C-terminal HTH domain is positioned between 18S rRNA helices h16 and h33, while an N-terminal Ξ±-helix contacts the base of h16 and ribosomal proteins uS4 and eS30. EDF1 also engages h18 and contacts uS3 near the mRNA entry channel
GO:0140467 integrated stress response signaling
IMP
PMID:39566505
Multiprotein bridging factor 1 is required for robust activa...
NEW
Summary: NEW annotation. EDF1 (and its yeast homolog Mbf1) is required for robust activation of the integrated stress response on collided ribosomes, mediating Gcn2/GCN2-dependent eIF2Ξ± phosphorylation rather than acting as a nuclear coactivator of GCN4/ATF4.
Reason: 2024 mechanistic work (PMID:39566505) reframes Mbf1/EDF1 as a core ISR factor that operates at collided ribosomes; this complements the RQC role and is supported by biochemical/genetic evidence in yeast with cell-fractionation evidence in human cells.
Supporting Evidence:
PMID:39566505
Mbf1 functions as a core ISR factor by interacting with collided ribosomes to mediate Gcn2 activation.
PMID:39566505
Mbf1 is required for optimal stress-induced eukaryotic initiation factor 2Ξ± (eIF2Ξ±) phosphorylation and downstream de-repression of GCN4 translation.
file:human/EDF1/EDF1-deep-research-falcon.md
EDF1/Mbf1 acts at collided ribosomes to promote robust ISR signaling

Core Functions

EDF1 is an evolutionarily conserved transcriptional coactivator that bridges gene-specific transcription factors (nuclear receptors NR5A1, NR1H3, PPARg; bZIP factors ATF1, ATF2, CREB1) to the TATA-binding protein (TBP) component of the general transcription machinery [PMID:10567391, PMID:12040021].

EDF1 contains an IQ motif that mediates calcium- and phosphorylation-dependent binding to calmodulin. This regulates eNOS activity in endothelial cells by sequestering calmodulin in the cytoplasm [PMID:10816571, PMID:15112053].

Molecular Function:
calmodulin binding

Direct binding to TBP and the TFIID complex is central to EDF1's bridging function between activators and the basal transcription machinery [PMID:10567391, PMID:12040021].

EDF1 was identified as an mRNA-binding protein in two independent proteomics studies [PMID:22658674, PMID:22681889]. This is consistent with its role at collided ribosomes where structural studies show it contacts mRNA and recruits the GIGYF2-eIF4E2 complex to enforce ribosome-associated quality control on stalled messages.

EDF1 binds collided ribosomes at a conserved 40S-subunit site near the mRNA entry channel (cryo-EM resolved at 2.9 Γ… in human 80S complex), contacting rRNA helices h16/h18/h33 and ribosomal proteins uS3/uS4/eS30. Recruitment is ZNF598-independent but RACK1-dependent, and EDF1 in turn recruits the cap-dependent translational repressors GIGYF2/EIF4E2 to suppress new initiation on defective mRNAs and facilitates ZNF598-mediated eS10/uS10 ubiquitylation as well as ZAKΞ±β†’p38 ribotoxic stress signalling [PMID:32744497, PMID:39566505].

Supporting Evidence:
  • PMID:32744497
    Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface.
  • PMID:39566505
    Given that Mbf1 and its human homologue EDF1 bind collided ribosomes using similar mechanisms, we hypothesized that EDF1 would also exert its effects primarily in the cytoplasm.

References

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Deep Research

Falcon

(EDF1-deep-research-falcon.md)

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OpenAI

(EDF1-deep-research-openai.md)

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