ATFS-1 (Activating Transcription Factor associated with Stress-1) is a bZIP transcription factor that serves as the master regulator of the mitochondrial unfolded protein response (UPRmt) in C. elegans. The protein contains dual targeting signals: an N-terminal mitochondrial targeting sequence (MTS, residues 1-23) and a nuclear localization signal (NLS, residues 436-441). Under normal conditions, ATFS-1 is efficiently imported into mitochondria and degraded by the Lon protease (LONP-1) in the matrix. During mitochondrial stress, when protein import efficiency is reduced, ATFS-1 accumulates in the cytosol and translocates to the nucleus where it activates transcription of UPRmt target genes including mitochondrial chaperones (hsp-6, hsp-60), proteases, import machinery components, innate immune effectors (abf-2, lys-2), and metabolic enzymes. This import-efficiency sensing mechanism allows cells to monitor mitochondrial health and mount protective responses. ATFS-1 also regulates mitochondrial transcription by binding mtDNA-encoded OXPHOS gene promoters. The UPRmt provides protection against pathogen infection (particularly P. aeruginosa), anoxia-reperfusion injury, and oxidative stress. ATFS-1 activity is modulated by SUMOylation at K342, with desumoylation by ULP-4 enhancing transcriptional activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: ATFS-1 is a bZIP transcription factor that binds DNA to regulate transcription. The IBA annotation is based on phylogenetic inference from related ATF family members. ATFS-1 has been shown by ChIP-seq to bind directly to OXPHOS gene promoters in both nuclear and mitochondrial genomes (PMID:25773600). Reason: The bZIP domain (residues 420-483) in ATFS-1 mediates sequence-specific DNA binding. ChIP-seq studies demonstrated direct binding to target gene promoters. This is a core molecular function annotation. Supporting Evidence: PMID:25773600 ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes file:worm/atfs-1/atfs-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: ATFS-1 functions as a transcriptional activator of UPRmt target genes including mitochondrial chaperones, proteases, and innate immune genes. Reason: Strong experimental evidence supports ATFS-1 as a transcriptional activator. Nuclear ATFS-1 activates transcription of hsp-6, hsp-60, and other protective genes. IBA annotation is well-supported by direct experimental evidence in this species. Supporting Evidence: PMID:22700657 we examined the mechanism by which ATFS-1 (activating transcription factor associated with stress-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans PMID:25274306 during mitochondrial stress ATFS-1 induced not only mitochondrial protective genes but also innate immune genes that included a secreted lysozyme and anti-microbial peptides |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: ATFS-1 localizes to the nucleus under mitochondrial stress conditions where it activates transcription of UPRmt target genes. Multiple IDA annotations support this. Reason: Nuclear localization is central to ATFS-1 function. The protein contains an NLS (residues 436-441) and accumulates in the nucleus when mitochondrial import is impaired. This is extensively documented by multiple studies. Supporting Evidence: PMID:22700657 during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ATFS-1 regulates transcription as a bZIP transcription factor, activating UPRmt target genes in the nucleus during mitochondrial stress. Reason: Core biological process annotation. ATFS-1 is a well-characterized transcription factor that regulates RNA polymerase II-dependent transcription of nuclear-encoded mitochondrial genes. Supporting Evidence: PMID:25773600 ATFS-1 stimulates respiratory recovery by fine-tuning OXPHOS expression |
| GO:0002376 immune system process | IEA GO_REF:0000043 | MODIFY | Summary: IEA annotation from UniProtKB keyword mapping. ATFS-1 has been experimentally shown to regulate innate immune genes during mitochondrial stress and pathogen exposure. Reason: The term is too general. ATFS-1 specifically regulates innate immunity in the context of UPRmt activation, not general immune system processes. More specific terms like 'innate immune response' (GO:0045087) or 'defense response to Gram-negative bacterium' (GO:0050829) are already annotated with experimental evidence. Proposed replacements: innate immune response |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for general DNA binding. ATFS-1 contains a bZIP DNA-binding domain and binds target gene promoters. Reason: While this term is general, it is not incorrect. The more specific term GO:0000977 (RNA polymerase II transcription regulatory region sequence-specific DNA binding) provides additional specificity, but this general term is acceptable as a broader classification. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro bZIP domain. ATFS-1 is indeed a DNA-binding transcription factor. Reason: Correct annotation based on domain architecture. The bZIP domain confers DNA-binding transcription factor activity. More specific terms are also present. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for nuclear localization. Duplicates IBA and IDA annotations for the same term. Reason: Correct annotation. Duplicates are acceptable as they represent different evidence sources. Nuclear localization is central to ATFS-1 function under stress conditions. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: ATFS-1 transits through the cytoplasm between its sites of action. Under normal conditions it is rapidly imported to mitochondria; under stress it accumulates transiently in the cytosol before nuclear import. Reason: Cytoplasmic localization is a transient state during ATFS-1 trafficking. The protein passes through the cytosol en route to either mitochondria or nucleus. Supporting Evidence: PMID:22700657 during mitochondrial stress...allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: ATFS-1 is imported into the mitochondrial matrix under normal conditions where it is degraded by the Lon protease LONP-1. Reason: Mitochondrial matrix localization is central to the ATFS-1 regulatory mechanism. The protein is constitutively imported and degraded under homeostatic conditions. Supporting Evidence: PMID:22700657 Normally, ATFS-1 is imported into mitochondria and degraded |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: General transcription annotation. ATFS-1 regulates DNA-templated transcription as a transcription factor. Reason: Correct but general annotation. More specific annotations for regulation of transcription are present with experimental evidence. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro. ATFS-1 regulates transcription of nuclear and mitochondrial genes. Reason: Correct annotation based on bZIP domain function. ATFS-1 is a well-characterized transcriptional regulator. |
| GO:0006390 mitochondrial transcription | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred from mitochondrial transcription factor activity annotation (GO:0034246). ATFS-1 has been shown by ChIP-seq to bind mtDNA-encoded OXPHOS gene promoters. Reason: ATFS-1 regulates both nuclear and mitochondrial transcription. ChIP-seq data demonstrated direct binding to mtDNA promoters. This is a unique function that coordinates nuclear and mitochondrial genome expression. Supporting Evidence: PMID:25773600 ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes |
| GO:0006986 response to unfolded protein | IEA GO_REF:0000043 | MODIFY | Summary: ATFS-1 mediates the mitochondrial unfolded protein response (UPRmt), a specialized response to misfolded proteins in mitochondria. Reason: While ATFS-1 does respond to unfolded proteins, this term is too general. The more specific term 'mitochondrial unfolded protein response' (GO:0034514) is more appropriate and is already annotated with IMP evidence. Proposed replacements: mitochondrial unfolded protein response |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: ATFS-1 activates innate immune gene expression during mitochondrial stress and pathogen exposure, including antimicrobial peptides (abf-2) and lysozymes (lys-2). Reason: Appropriate annotation. ATFS-1 regulates innate immunity as part of its UPRmt function, providing resistance to pathogens like P. aeruginosa. Supporting Evidence: PMID:25274306 ATFS-1 induced not only mitochondrial protective genes but also innate immune genes that included a secreted lysozyme and anti-microbial peptides |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred from DNA-binding transcription activator activity annotation. ATFS-1 positively regulates transcription of UPRmt target genes. Reason: Correct inference. ATFS-1 activates transcription of mitochondrial chaperones, proteases, import machinery, and innate immune genes. Supporting Evidence: PMID:22700657 we examined the mechanism by which ATFS-1 (activating transcription factor associated with stress-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans |
| GO:0005515 protein binding | IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | MARK AS OVER ANNOTATED | Summary: IPI annotation based on bZIP dimerization study. ATFS-1 interacts with CEBP-2 (C/EBP family) in a large-scale bZIP protein-protein interaction study. Reason: 'Protein binding' is too general and uninformative. The actual interaction with CEBP-2 suggests bZIP dimerization activity. A more specific term like 'DNA-binding transcription factor binding' or 'bZIP transcription factor binding' would be more appropriate, but the study was a high-throughput screen without functional validation of specific interactions. Supporting Evidence: PMID:23661758 We studied the basic region-leucine zipper (bZIP) transcription factors and quantified bZIP dimerization networks |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IDA evidence from Nargund et al. 2015 demonstrating that ATFS-1 activates transcription of UPRmt target genes including mitochondrial chaperones and OXPHOS genes. Reason: High-quality direct experimental evidence. ChIP-seq showed ATFS-1 binding to target promoters, and functional studies demonstrated transcriptional activation. Supporting Evidence: PMID:25773600 in addition to regulating mitochondrial chaperone, OXPHOS complex assembly factor, and glycolysis genes, ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes |
| GO:0005634 nucleus | IDA PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UP... | ACCEPT | Summary: IDA evidence from the foundational Haynes et al. 2010 paper identifying ZC376.7 (ATFS-1) as a bZIP transcription factor that localizes to nuclei during mitochondrial stress. Reason: Original experimental demonstration of nuclear localization during UPRmt. This paper first identified ATFS-1 as the transcription factor mediating UPRmt. Supporting Evidence: PMID:20188671 Defective UPR(mt) signaling in the haf-1-deleted worms was associated with failure of the bZIP protein, ZC376.7, to localize to nuclei |
| GO:0005634 nucleus | IDA PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: IDA evidence from Pellegrino et al. 2014 showing ATFS-1 nuclear accumulation during P. aeruginosa infection. Reason: Direct visualization showed increased nuclear accumulation of ATFS-1::GFP during pathogen exposure. Supporting Evidence: PMID:25274306 P. aeruginosa exposure caused...increased nuclear accumulation of ATFS-1::GFP |
| GO:0005634 nucleus | IDA PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IDA evidence from Nargund et al. 2015 demonstrating nuclear ATFS-1 accumulation and function during UPRmt. Reason: ChIP-seq demonstrated ATFS-1 binding to nuclear gene promoters, confirming nuclear localization and function. Supporting Evidence: PMID:25773600 balanced ATFS-1 accumulation promoted OXPHOS complex assembly and function...which required accumulation of ATFS-1 in the nucleus and mitochondria |
| GO:0034514 mitochondrial unfolded protein response | IGI PMID:22719267 Protective coupling of mitochondrial function and protein sy... | ACCEPT | Summary: IGI annotation from a study examining protective coupling of mitochondrial function and protein synthesis via GCN-2. Reason: ATFS-1 is the master regulator of UPRmt. Genetic interaction studies support its role in this pathway. Supporting Evidence: PMID:22719267 Jun 14. Protective coupling of mitochondrial function and protein synthesis via the eIF2Ξ± kinase GCN-2. |
| GO:0005654 nucleoplasm | TAS Reactome:R-CEL-9856623 | ACCEPT | Summary: TAS annotation from Reactome pathway annotation. ATFS-1 translocates from cytosol to nucleoplasm during UPRmt activation. Reason: Consistent with known biology. When ATFS-1 enters the nucleus, it is active in the nucleoplasm where it binds DNA. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-CEL-9856612 | ACCEPT | Summary: TAS annotation from Reactome pathway. ATFS-1 is imported to the mitochondrial matrix under normal conditions. Reason: Correct annotation. ATFS-1 contains an MTS that targets it to the matrix where it is degraded by Lon protease. |
| GO:0005829 cytosol | TAS Reactome:R-CEL-9856612 | ACCEPT | Summary: TAS annotation from Reactome. ATFS-1 transits through cytosol before mitochondrial import. Reason: Correct annotation. The protein passes through the cytosol during its trafficking to mitochondria or nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-CEL-9856623 | ACCEPT | Summary: TAS annotation from Reactome. ATFS-1 accumulates in cytosol during stress before nuclear translocation. Reason: Correct annotation. Under stress conditions, ATFS-1 accumulates in cytosol when mitochondrial import is reduced. |
| GO:0005634 nucleus | HDA PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UP... | ACCEPT | Summary: HDA (high-throughput direct assay) annotation for nuclear localization. Reason: Consistent with IDA evidence from the same publication demonstrating nuclear localization during UPRmt. Supporting Evidence: PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. |
| GO:0005634 nucleus | IDA PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon... | ACCEPT | Summary: IDA evidence from the landmark Nargund et al. 2012 Science paper establishing the mitochondrial import efficiency model for ATFS-1 regulation. Reason: Key paper demonstrating that reduced mitochondrial import allows ATFS-1 to traffic to the nucleus. Supporting Evidence: PMID:22700657 during mitochondrial stress...import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus |
| GO:0019899 enzyme binding | IPI PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated in... | ACCEPT | Summary: IPI annotation based on interaction with ULP-4, a SUMO peptidase that desumoylates ATFS-1 at K342. Reason: Valid interaction. ULP-4 is a SUMO peptidase (an enzyme) that directly interacts with and desumoylates ATFS-1, enhancing its transcriptional activity. Supporting Evidence: PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated innate immunity and lifespan extension. |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated in... | ACCEPT | Summary: IMP evidence from Gao et al. 2019 showing that SUMOylation of ATFS-1 regulates UPRmt. Reason: Demonstrates that ATFS-1 SUMOylation at K342 modulates UPRmt activation, with desumoylation enhancing the response. Supporting Evidence: PMID:30642431 SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated innate immunity and lifespan extension. |
| GO:0050829 defense response to Gram-negative bacterium | IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: IGI annotation for genetic interaction in defense against P. aeruginosa (a Gram-negative bacterium). Reason: ATFS-1 was shown to interact genetically with other genes to provide resistance to P. aeruginosa infection. Supporting Evidence: PMID:25274306 hyper-activation of ATFS-1 and the UPR(mt) improved clearance of P. aeruginosa from the intestine and prolonged C. elegans survival |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:30057120 The Mitochondrial Unfolded Protein Response Is Mediated Cell... | ACCEPT | Summary: IMP evidence from Zhang et al. 2018 Cell paper showing ATFS-1 role in cell-non-autonomous UPRmt mediated by Wnt signaling. Reason: Key paper demonstrating that UPRmt can be propagated cell-non-autonomously via retromer-dependent Wnt signaling, with ATFS-1 as the central regulator. Supporting Evidence: PMID:30057120 The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion across multiple tissues |
| GO:0010468 regulation of gene expression | IMP PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon... | ACCEPT | Summary: IMP evidence for regulation of gene expression from the landmark 2012 Science paper. Reason: Core function annotation. ATFS-1 regulates expression of hundreds of target genes during UPRmt activation. Supporting Evidence: PMID:22700657 cells monitor mitochondrial import efficiency via ATFS-1 to coordinate the level of mitochondrial dysfunction with the protective transcriptional response |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon... | ACCEPT | Summary: IMP evidence from the foundational 2012 Science paper establishing ATFS-1 as the key regulator of UPRmt. Reason: Core function annotation from the key paper demonstrating the import-efficiency sensing mechanism. Supporting Evidence: PMID:22700657 ATFS-1 (activating transcription factor associated with stress-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPR(mt)) |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IMP evidence for transcription factor activity from Nargund et al. 2015. Reason: Core molecular function annotation. ChIP-seq and transcriptomics demonstrated ATFS-1 binds target gene promoters and regulates their expression. Supporting Evidence: PMID:25773600 in addition to regulating mitochondrial chaperone, OXPHOS complex assembly factor, and glycolysis genes, ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes |
| GO:0005634 nucleus | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IMP evidence for nuclear localization from functional studies. Reason: Mutant phenotype analysis showed that nuclear ATFS-1 is required for OXPHOS recovery during UPRmt. Supporting Evidence: PMID:25773600 atfs-1 was required to limit the accumulation of OXPHOS transcripts during mitochondrial stress, which required accumulation of ATFS-1 in the nucleus and mitochondria |
| GO:0005759 mitochondrial matrix | IMP PMID:22700657 Mitochondrial import efficiency of ATFS-1 regulates mitochon... | ACCEPT | Summary: IMP evidence for mitochondrial matrix localization under normal conditions. Reason: The import-efficiency model depends on ATFS-1 being imported to and degraded in the mitochondrial matrix under homeostatic conditions. Supporting Evidence: PMID:22700657 Normally, ATFS-1 is imported into mitochondria and degraded |
| GO:0005759 mitochondrial matrix | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IMP evidence for mitochondrial matrix localization and function. Reason: ATFS-1 functions in both mitochondria and nucleus, with balanced accumulation required for OXPHOS recovery. Supporting Evidence: PMID:25773600 balanced ATFS-1 accumulation promoted OXPHOS complex assembly and function |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IMP evidence for regulation of Pol II-dependent transcription. Reason: ChIP-seq and gene expression studies demonstrated ATFS-1 regulates nuclear Pol II-transcribed genes. Supporting Evidence: PMID:25773600 atfs-1 was required to limit the accumulation of OXPHOS transcripts during mitochondrial stress |
| GO:0034246 mitochondrial transcription factor activity | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IMP evidence for mitochondrial transcription factor activity from ChIP-seq showing ATFS-1 binding to mtDNA promoters. Reason: Unique function - ATFS-1 is one of few transcription factors known to regulate both nuclear and mitochondrial gene expression. Supporting Evidence: PMID:25773600 ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: IMP evidence from pathogen infection studies showing ATFS-1 mediates UPRmt during P. aeruginosa exposure. Reason: Demonstrates that UPRmt activation by pathogen-induced mitochondrial stress requires ATFS-1. Supporting Evidence: PMID:25274306 Exposure to the pathogen Pseudomonas aeruginosa caused mitochondrial dysfunction and activation of the UPR(mt) |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IMP evidence for UPRmt function from comprehensive characterization of ATFS-1 target genes. Reason: Core function annotation with strong experimental support. Supporting Evidence: PMID:25773600 ATFS-1, a transcription factor that regulates mitochondria-to-nuclear communication during the mitochondrial UPR |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:27459203 The Mitochondrial Unfolded Protein Response Protects against... | ACCEPT | Summary: IMP evidence from Pena et al. 2016 showing UPRmt protects against anoxia in an ATFS-1-dependent manner. Reason: Demonstrates that atfs-1 is both necessary and sufficient for UPRmt activation and protection from anoxia-reperfusion injury. Supporting Evidence: PMID:27459203 atfs-1 gain-of-function (gf) mutants...exhibited constitutive induction of the UPRmt reporter gene hsp-60 |
| GO:1903108 regulation of mitochondrial transcription | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | ACCEPT | Summary: IMP evidence for regulation of mitochondrial transcription from ChIP-seq demonstrating ATFS-1 binding to mtDNA promoters. Reason: Key finding that ATFS-1 regulates both nuclear and mitochondrial genomes during UPRmt activation. Supporting Evidence: PMID:25773600 ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes |
| GO:0010468 regulation of gene expression | IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: IGI evidence for genetic interaction in regulating gene expression during pathogen response. Reason: Demonstrates that ATFS-1 interacts with other genes to regulate innate immune gene expression. Supporting Evidence: PMID:25274306 induction of innate immune genes by spg-7(RNAi) required ATFS-1 |
| GO:0010628 positive regulation of gene expression | IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: IMP evidence for positive regulation of innate immune and mitochondrial protective genes. Reason: ATFS-1 activates transcription of target genes including abf-2, lys-2, hsp-6, and hsp-60. Supporting Evidence: PMID:25274306 ATFS-1 induced not only mitochondrial protective genes but also innate immune genes |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: IMP evidence for role in defense against P. aeruginosa from survival and pathogen clearance assays. Reason: atfs-1 loss-of-function worms are susceptible to P. aeruginosa, while gain-of-function mutants show enhanced resistance. Supporting Evidence: PMID:25274306 C. elegans lacking atfs-1 were susceptible to P. aeruginosa, whereas hyper-activation of ATFS-1 and the UPR(mt) improved clearance of P. aeruginosa from the intestine |
| GO:0003700 DNA-binding transcription factor activity | ISS PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UP... | ACCEPT | Summary: ISS annotation based on sequence similarity to mammalian ATF family members. Reason: Appropriate annotation based on bZIP domain and functional similarity. Now supported by direct experimental evidence in C. elegans. Supporting Evidence: PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UP... | ACCEPT | Summary: IMP evidence from the foundational paper first identifying ZC376.7 (ATFS-1) as the UPRmt transcription factor. Reason: Original identification of ATFS-1 function in UPRmt. RNAi strongly inhibited the UPRmt. Supporting Evidence: PMID:20188671 zc376.7(RNAi) strongly inhibited the UPR(mt) |
| GO:0005737 cytoplasm | HDA PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UP... | ACCEPT | Summary: HDA annotation for cytoplasmic localization. Reason: ATFS-1 transits through cytoplasm during its regulated trafficking. Supporting Evidence: PMID:20188671 The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. |
| GO:0097009 energy homeostasis | IMP PMID:25773600 Mitochondrial and nuclear accumulation of the transcription ... | NEW | Summary: ATFS-1 coordinates OXPHOS gene expression during mitochondrial stress to maintain energy homeostasis. The protein fine-tunes OXPHOS expression to match the capacity of stressed mitochondria. Reason: Core function not explicitly annotated. ATFS-1 coordinates mitochondrial and nuclear genome expression to maintain respiratory capacity during stress. Supporting Evidence: PMID:25773600 ATFS-1 stimulates respiratory recovery by fine-tuning OXPHOS expression to match the capacity of the suboptimal protein-folding environment in stressed mitochondria |
| GO:0034599 cellular response to oxidative stress | IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | NEW | Summary: ATFS-1 and UPRmt activation provide protection against oxidative stress. The regulon includes ROS detoxification genes. Reason: UPRmt activation protects against multiple stressors including oxidative stress. The deep research indicates ATFS-1 induces ROS detoxification genes. Supporting Evidence: PMID:25274306 ATFS-1 induces genes that promote mitochondrial protein folding, ROS detoxification and mitochondrial protein import |
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Q: How do ATFS-1, DVE-1, and UBL-5 cooperate in UPRmt activation?
Q: What determines whether ATFS-1 promotes mitophagy versus UPRmt?
Q: What is the mammalian functional ortholog of ATFS-1?
Experiment: ChIP-seq in different stress conditions to map the complete ATFS-1 regulon
Experiment: Structure-function analysis of ATFS-1 domains for nuclear vs mitochondrial function
Experiment: Single-cell analysis of ATFS-1 localization dynamics during stress
Experiment: Genetic screens for ATFS-1 cofactors in specific tissue contexts
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