id: Q23272
gene_symbol: atfs-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: '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.'
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: 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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: ATFS-1 bound directly to OXPHOS gene promoters in both 
        the nuclear and mitochondrial genomes
    - reference_id: file:worm/atfs-1/atfs-1-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- 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: ATFS-1 functions as a transcriptional activator of UPRmt target 
      genes including mitochondrial chaperones, proteases, and innate immune 
      genes.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: 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
    - reference_id: PMID:25274306
      supporting_text: 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
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ATFS-1 localizes to the nucleus under mitochondrial stress 
      conditions where it activates transcription of UPRmt target genes. 
      Multiple IDA annotations support this.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: 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
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ATFS-1 regulates transcription as a bZIP transcription factor, 
      activating UPRmt target genes in the nucleus during mitochondrial stress.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: ATFS-1 stimulates respiratory recovery by fine-tuning 
        OXPHOS expression
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation from UniProtKB keyword mapping. ATFS-1 has been 
      experimentally shown to regulate innate immune genes during mitochondrial 
      stress and pathogen exposure.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0045087
      label: innate immune response
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation for general DNA binding. ATFS-1 contains a bZIP 
      DNA-binding domain and binds target gene promoters.
    action: ACCEPT
    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.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation from InterPro bZIP domain. ATFS-1 is indeed a 
      DNA-binding transcription factor.
    action: ACCEPT
    reason: Correct annotation based on domain architecture. The bZIP domain 
      confers DNA-binding transcription factor activity. More specific terms are
      also present.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation for nuclear localization. Duplicates IBA and IDA 
      annotations for the same term.
    action: ACCEPT
    reason: Correct annotation. Duplicates are acceptable as they represent 
      different evidence sources. Nuclear localization is central to ATFS-1 
      function under stress conditions.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    reason: Cytoplasmic localization is a transient state during ATFS-1 
      trafficking. The protein passes through the cytosol en route to either 
      mitochondria or nucleus.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: during mitochondrial stress...allowing a percentage of 
        ATFS-1 to accumulate in the cytosol and traffic to the nucleus
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: ATFS-1 is imported into the mitochondrial matrix under normal 
      conditions where it is degraded by the Lon protease LONP-1.
    action: ACCEPT
    reason: Mitochondrial matrix localization is central to the ATFS-1 
      regulatory mechanism. The protein is constitutively imported and degraded 
      under homeostatic conditions.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: Normally, ATFS-1 is imported into mitochondria and 
        degraded
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: General transcription annotation. ATFS-1 regulates DNA-templated 
      transcription as a transcription factor.
    action: ACCEPT
    reason: Correct but general annotation. More specific annotations for 
      regulation of transcription are present with experimental evidence.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation from InterPro. ATFS-1 regulates transcription of 
      nuclear and mitochondrial genes.
    action: ACCEPT
    reason: Correct annotation based on bZIP domain function. ATFS-1 is a 
      well-characterized transcriptional regulator.
- term:
    id: GO:0006390
    label: mitochondrial transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: ATFS-1 bound directly to OXPHOS gene promoters in both 
        the nuclear and mitochondrial genomes
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: ATFS-1 mediates the mitochondrial unfolded protein response 
      (UPRmt), a specialized response to misfolded proteins in mitochondria.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0034514
      label: mitochondrial unfolded protein response
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: ATFS-1 activates innate immune gene expression during mitochondrial
      stress and pathogen exposure, including antimicrobial peptides (abf-2) and
      lysozymes (lys-2).
    action: ACCEPT
    reason: Appropriate annotation. ATFS-1 regulates innate immunity as part of 
      its UPRmt function, providing resistance to pathogens like P. aeruginosa.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: ATFS-1 induced not only mitochondrial protective genes 
        but also innate immune genes that included a secreted lysozyme and 
        anti-microbial peptides
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: Inferred from DNA-binding transcription activator activity 
      annotation. ATFS-1 positively regulates transcription of UPRmt target 
      genes.
    action: ACCEPT
    reason: Correct inference. ATFS-1 activates transcription of mitochondrial 
      chaperones, proteases, import machinery, and innate immune genes.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23661758
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.'
    supported_by:
    - reference_id: PMID:23661758
      supporting_text: We studied the basic region-leucine zipper (bZIP) 
        transcription factors and quantified bZIP dimerization networks
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase 
      II-specific
  evidence_type: IDA
  original_reference_id: PMID:25773600
  review:
    summary: IDA evidence from Nargund et al. 2015 demonstrating that ATFS-1 
      activates transcription of UPRmt target genes including mitochondrial 
      chaperones and OXPHOS genes.
    action: ACCEPT
    reason: High-quality direct experimental evidence. ChIP-seq showed ATFS-1 
      binding to target promoters, and functional studies demonstrated 
      transcriptional activation.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: 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
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:20188671
  review:
    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.
    action: ACCEPT
    reason: Original experimental demonstration of nuclear localization during 
      UPRmt. This paper first identified ATFS-1 as the transcription factor 
      mediating UPRmt.
    supported_by:
    - reference_id: PMID:20188671
      supporting_text: Defective UPR(mt) signaling in the haf-1-deleted worms 
        was associated with failure of the bZIP protein, ZC376.7, to localize to
        nuclei
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25274306
  review:
    summary: IDA evidence from Pellegrino et al. 2014 showing ATFS-1 nuclear 
      accumulation during P. aeruginosa infection.
    action: ACCEPT
    reason: Direct visualization showed increased nuclear accumulation of 
      ATFS-1::GFP during pathogen exposure.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: P. aeruginosa exposure caused...increased nuclear 
        accumulation of ATFS-1::GFP
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25773600
  review:
    summary: IDA evidence from Nargund et al. 2015 demonstrating nuclear ATFS-1 
      accumulation and function during UPRmt.
    action: ACCEPT
    reason: ChIP-seq demonstrated ATFS-1 binding to nuclear gene promoters, 
      confirming nuclear localization and function.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: balanced ATFS-1 accumulation promoted OXPHOS complex 
        assembly and function...which required accumulation of ATFS-1 in the 
        nucleus and mitochondria
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IGI
  original_reference_id: PMID:22719267
  review:
    summary: IGI annotation from a study examining protective coupling of 
      mitochondrial function and protein synthesis via GCN-2.
    action: ACCEPT
    reason: ATFS-1 is the master regulator of UPRmt. Genetic interaction studies
      support its role in this pathway.
    supported_by:
    - reference_id: PMID:22719267
      supporting_text: Jun 14. Protective coupling of mitochondrial function and
        protein synthesis via the eIF2α kinase GCN-2.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-CEL-9856623
  review:
    summary: TAS annotation from Reactome pathway annotation. ATFS-1 
      translocates from cytosol to nucleoplasm during UPRmt activation.
    action: ACCEPT
    reason: Consistent with known biology. When ATFS-1 enters the nucleus, it is
      active in the nucleoplasm where it binds DNA.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-CEL-9856612
  review:
    summary: TAS annotation from Reactome pathway. ATFS-1 is imported to the 
      mitochondrial matrix under normal conditions.
    action: ACCEPT
    reason: Correct annotation. ATFS-1 contains an MTS that targets it to the 
      matrix where it is degraded by Lon protease.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-CEL-9856612
  review:
    summary: TAS annotation from Reactome. ATFS-1 transits through cytosol 
      before mitochondrial import.
    action: ACCEPT
    reason: Correct annotation. The protein passes through the cytosol during 
      its trafficking to mitochondria or nucleus.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-CEL-9856623
  review:
    summary: TAS annotation from Reactome. ATFS-1 accumulates in cytosol during 
      stress before nuclear translocation.
    action: ACCEPT
    reason: Correct annotation. Under stress conditions, ATFS-1 accumulates in 
      cytosol when mitochondrial import is reduced.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:20188671
  review:
    summary: HDA (high-throughput direct assay) annotation for nuclear 
      localization.
    action: ACCEPT
    reason: Consistent with IDA evidence from the same publication demonstrating
      nuclear localization during UPRmt.
    supported_by:
    - reference_id: PMID:20188671
      supporting_text: The matrix peptide exporter HAF-1 signals a mitochondrial
        UPR by activating the transcription factor ZC376.7 in C.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22700657
  review:
    summary: IDA evidence from the landmark Nargund et al. 2012 Science paper 
      establishing the mitochondrial import efficiency model for ATFS-1 
      regulation.
    action: ACCEPT
    reason: Key paper demonstrating that reduced mitochondrial import allows 
      ATFS-1 to traffic to the nucleus.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: during mitochondrial stress...import efficiency was 
        reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol 
        and traffic to the nucleus
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:30642431
  review:
    summary: IPI annotation based on interaction with ULP-4, a SUMO peptidase 
      that desumoylates ATFS-1 at K342.
    action: ACCEPT
    reason: Valid interaction. ULP-4 is a SUMO peptidase (an enzyme) that 
      directly interacts with and desumoylates ATFS-1, enhancing its 
      transcriptional activity.
    supported_by:
    - reference_id: PMID:30642431
      supporting_text: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated
        innate immunity and lifespan extension.
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:30642431
  review:
    summary: IMP evidence from Gao et al. 2019 showing that SUMOylation of 
      ATFS-1 regulates UPRmt.
    action: ACCEPT
    reason: Demonstrates that ATFS-1 SUMOylation at K342 modulates UPRmt 
      activation, with desumoylation enhancing the response.
    supported_by:
    - reference_id: PMID:30642431
      supporting_text: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated
        innate immunity and lifespan extension.
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IGI
  original_reference_id: PMID:25274306
  review:
    summary: IGI annotation for genetic interaction in defense against P. 
      aeruginosa (a Gram-negative bacterium).
    action: ACCEPT
    reason: ATFS-1 was shown to interact genetically with other genes to provide
      resistance to P. aeruginosa infection.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: hyper-activation of ATFS-1 and the UPR(mt) improved 
        clearance of P. aeruginosa from the intestine and prolonged C. elegans 
        survival
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:30057120
  review:
    summary: IMP evidence from Zhang et al. 2018 Cell paper showing ATFS-1 role 
      in cell-non-autonomous UPRmt mediated by Wnt signaling.
    action: ACCEPT
    reason: Key paper demonstrating that UPRmt can be propagated 
      cell-non-autonomously via retromer-dependent Wnt signaling, with ATFS-1 as
      the central regulator.
    supported_by:
    - reference_id: PMID:30057120
      supporting_text: The mitochondrial unfolded protein response (UPRmt) can 
        be triggered in a cell-non-autonomous fashion across multiple tissues
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:22700657
  review:
    summary: IMP evidence for regulation of gene expression from the landmark 
      2012 Science paper.
    action: ACCEPT
    reason: Core function annotation. ATFS-1 regulates expression of hundreds of
      target genes during UPRmt activation.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: cells monitor mitochondrial import efficiency via ATFS-1 
        to coordinate the level of mitochondrial dysfunction with the protective
        transcriptional response
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:22700657
  review:
    summary: IMP evidence from the foundational 2012 Science paper establishing 
      ATFS-1 as the key regulator of UPRmt.
    action: ACCEPT
    reason: Core function annotation from the key paper demonstrating the 
      import-efficiency sensing mechanism.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: 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))
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    summary: IMP evidence for transcription factor activity from Nargund et al. 
      2015.
    action: ACCEPT
    reason: Core molecular function annotation. ChIP-seq and transcriptomics 
      demonstrated ATFS-1 binds target gene promoters and regulates their 
      expression.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: 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
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    summary: IMP evidence for nuclear localization from functional studies.
    action: ACCEPT
    reason: Mutant phenotype analysis showed that nuclear ATFS-1 is required for
      OXPHOS recovery during UPRmt.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: 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
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IMP
  original_reference_id: PMID:22700657
  review:
    summary: IMP evidence for mitochondrial matrix localization under normal 
      conditions.
    action: ACCEPT
    reason: The import-efficiency model depends on ATFS-1 being imported to and 
      degraded in the mitochondrial matrix under homeostatic conditions.
    supported_by:
    - reference_id: PMID:22700657
      supporting_text: Normally, ATFS-1 is imported into mitochondria and 
        degraded
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    summary: IMP evidence for mitochondrial matrix localization and function.
    action: ACCEPT
    reason: ATFS-1 functions in both mitochondria and nucleus, with balanced 
      accumulation required for OXPHOS recovery.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: balanced ATFS-1 accumulation promoted OXPHOS complex 
        assembly and function
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    summary: IMP evidence for regulation of Pol II-dependent transcription.
    action: ACCEPT
    reason: ChIP-seq and gene expression studies demonstrated ATFS-1 regulates 
      nuclear Pol II-transcribed genes.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: atfs-1 was required to limit the accumulation of OXPHOS 
        transcripts during mitochondrial stress
- term:
    id: GO:0034246
    label: mitochondrial transcription factor activity
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    summary: IMP evidence for mitochondrial transcription factor activity from 
      ChIP-seq showing ATFS-1 binding to mtDNA promoters.
    action: ACCEPT
    reason: Unique function - ATFS-1 is one of few transcription factors known 
      to regulate both nuclear and mitochondrial gene expression.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: ATFS-1 bound directly to OXPHOS gene promoters in both 
        the nuclear and mitochondrial genomes
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:25274306
  review:
    summary: IMP evidence from pathogen infection studies showing ATFS-1 
      mediates UPRmt during P. aeruginosa exposure.
    action: ACCEPT
    reason: Demonstrates that UPRmt activation by pathogen-induced mitochondrial
      stress requires ATFS-1.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: Exposure to the pathogen Pseudomonas aeruginosa caused 
        mitochondrial dysfunction and activation of the UPR(mt)
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    summary: IMP evidence for UPRmt function from comprehensive characterization
      of ATFS-1 target genes.
    action: ACCEPT
    reason: Core function annotation with strong experimental support.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: ATFS-1, a transcription factor that regulates 
        mitochondria-to-nuclear communication during the mitochondrial UPR
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:27459203
  review:
    summary: IMP evidence from Pena et al. 2016 showing UPRmt protects against 
      anoxia in an ATFS-1-dependent manner.
    action: ACCEPT
    reason: Demonstrates that atfs-1 is both necessary and sufficient for UPRmt 
      activation and protection from anoxia-reperfusion injury.
    supported_by:
    - reference_id: PMID:27459203
      supporting_text: atfs-1 gain-of-function (gf) mutants...exhibited 
        constitutive induction of the UPRmt reporter gene hsp-60
- term:
    id: GO:1903108
    label: regulation of mitochondrial transcription
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    summary: IMP evidence for regulation of mitochondrial transcription from 
      ChIP-seq demonstrating ATFS-1 binding to mtDNA promoters.
    action: ACCEPT
    reason: Key finding that ATFS-1 regulates both nuclear and mitochondrial 
      genomes during UPRmt activation.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: ATFS-1 bound directly to OXPHOS gene promoters in both 
        the nuclear and mitochondrial genomes
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:25274306
  review:
    summary: IGI evidence for genetic interaction in regulating gene expression 
      during pathogen response.
    action: ACCEPT
    reason: Demonstrates that ATFS-1 interacts with other genes to regulate 
      innate immune gene expression.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: induction of innate immune genes by spg-7(RNAi) required 
        ATFS-1
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:25274306
  review:
    summary: IMP evidence for positive regulation of innate immune and 
      mitochondrial protective genes.
    action: ACCEPT
    reason: ATFS-1 activates transcription of target genes including abf-2, 
      lys-2, hsp-6, and hsp-60.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: ATFS-1 induced not only mitochondrial protective genes 
        but also innate immune genes
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IMP
  original_reference_id: PMID:25274306
  review:
    summary: IMP evidence for role in defense against P. aeruginosa from 
      survival and pathogen clearance assays.
    action: ACCEPT
    reason: atfs-1 loss-of-function worms are susceptible to P. aeruginosa, 
      while gain-of-function mutants show enhanced resistance.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: 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
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: ISS
  original_reference_id: PMID:20188671
  review:
    summary: ISS annotation based on sequence similarity to mammalian ATF family
      members.
    action: ACCEPT
    reason: Appropriate annotation based on bZIP domain and functional 
      similarity. Now supported by direct experimental evidence in C. elegans.
    supported_by:
    - reference_id: PMID:20188671
      supporting_text: The matrix peptide exporter HAF-1 signals a mitochondrial
        UPR by activating the transcription factor ZC376.7 in C.
- term:
    id: GO:0034514
    label: mitochondrial unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:20188671
  review:
    summary: IMP evidence from the foundational paper first identifying ZC376.7 
      (ATFS-1) as the UPRmt transcription factor.
    action: ACCEPT
    reason: Original identification of ATFS-1 function in UPRmt. RNAi strongly 
      inhibited the UPRmt.
    supported_by:
    - reference_id: PMID:20188671
      supporting_text: zc376.7(RNAi) strongly inhibited the UPR(mt)
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:20188671
  review:
    summary: HDA annotation for cytoplasmic localization.
    action: ACCEPT
    reason: ATFS-1 transits through cytoplasm during its regulated trafficking.
    supported_by:
    - reference_id: PMID:20188671
      supporting_text: The matrix peptide exporter HAF-1 signals a mitochondrial
        UPR by activating the transcription factor ZC376.7 in C.
- term:
    id: GO:0097009
    label: energy homeostasis
  evidence_type: IMP
  original_reference_id: PMID:25773600
  review:
    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.
    action: NEW
    reason: Core function not explicitly annotated. ATFS-1 coordinates 
      mitochondrial and nuclear genome expression to maintain respiratory 
      capacity during stress.
    supported_by:
    - reference_id: PMID:25773600
      supporting_text: ATFS-1 stimulates respiratory recovery by fine-tuning 
        OXPHOS expression to match the capacity of the suboptimal 
        protein-folding environment in stressed mitochondria
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:25274306
  review:
    summary: ATFS-1 and UPRmt activation provide protection against oxidative 
      stress. The regulon includes ROS detoxification genes.
    action: NEW
    reason: UPRmt activation protects against multiple stressors including 
      oxidative stress. The deep research indicates ATFS-1 induces ROS 
      detoxification genes.
    supported_by:
    - reference_id: PMID:25274306
      supporting_text: ATFS-1 induces genes that promote mitochondrial protein 
        folding, ROS detoxification and mitochondrial protein import
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: IBA annotations supported by phylogenetic analysis of ATF/CREB 
      family bZIP transcription factors
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on 
    inter-ontology links
- id: PMID:20188671
  title: The matrix peptide exporter HAF-1 signals a mitochondrial UPR by 
    activating the transcription factor ZC376.7 in C. elegans.
  findings:
  - statement: First identification of ZC376.7 (now ATFS-1) as the bZIP 
      transcription factor mediating UPRmt
    supporting_text: The matrix peptide exporter HAF-1 signals a mitochondrial 
      UPR by activating the transcription factor ZC376.7 in C. elegans.
  - statement: HAF-1 is required for UPRmt signaling
    supporting_text: The matrix peptide exporter HAF-1 signals a mitochondrial 
      UPR by activating the transcription factor ZC376.7 in C. elegans.
  - statement: Nuclear localization of ATFS-1 depends on HAF-1 function during 
      mitochondrial stress
    supporting_text: The matrix peptide exporter HAF-1 signals a mitochondrial 
      UPR by activating the transcription factor ZC376.7 in C. elegans.
  - statement: ClpP-mediated peptide generation contributes to UPRmt signaling
    supporting_text: The matrix peptide exporter HAF-1 signals a mitochondrial 
      UPR by activating the transcription factor ZC376.7 in C. elegans.
- id: PMID:22700657
  title: Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR 
    activation.
  findings:
  - statement: Established the mitochondrial import efficiency model for ATFS-1 
      regulation
    supporting_text: Mitochondrial import efficiency of ATFS-1 regulates 
      mitochondrial UPR activation.
  - statement: ATFS-1 has both MTS and NLS sequences
    supporting_text: Mitochondrial import efficiency of ATFS-1 regulates 
      mitochondrial UPR activation.
  - statement: Normally imported to mitochondria and degraded by Lon protease
    supporting_text: Mitochondrial import efficiency of ATFS-1 regulates 
      mitochondrial UPR activation.
  - statement: Mitochondrial stress reduces import, allowing nuclear 
      translocation
    supporting_text: Mitochondrial import efficiency of ATFS-1 regulates 
      mitochondrial UPR activation.
  - statement: Cells monitor mitochondrial import efficiency via ATFS-1
    supporting_text: Mitochondrial import efficiency of ATFS-1 regulates 
      mitochondrial UPR activation.
- id: PMID:22719267
  title: "Protective coupling of mitochondrial function and protein synthesis via
    the eIF2α kinase GCN-2."
  findings:
  - statement: GCN-2 and ATFS-1 coordinate mitochondrial stress response
    supporting_text: Protective coupling of mitochondrial function and protein 
      synthesis via the eIF2α kinase GCN-2.
- id: PMID:23661758
  title: Networks of bZIP protein-protein interactions diversified over a 
    billion years of evolution.
  findings:
  - statement: Large-scale bZIP dimerization study
    supporting_text: Networks of bZIP protein-protein interactions diversified 
      over a billion years of evolution.
  - statement: ATFS-1 interacts with CEBP-2
    supporting_text: Networks of bZIP protein-protein interactions diversified 
      over a billion years of evolution.
- id: PMID:25274306
  title: Mitochondrial UPR-regulated innate immunity provides resistance to 
    pathogen infection.
  findings:
  - statement: ATFS-1 induces innate immune genes during mitochondrial stress
    supporting_text: Mitochondrial UPR-regulated innate immunity provides 
      resistance to pathogen infection.
  - statement: P. aeruginosa causes mitochondrial stress and UPRmt activation
    supporting_text: Mitochondrial UPR-regulated innate immunity provides 
      resistance to pathogen infection.
  - statement: atfs-1 mutants are susceptible to P. aeruginosa
    supporting_text: Mitochondrial UPR-regulated innate immunity provides 
      resistance to pathogen infection.
  - statement: atfs-1(et18) gain-of-function provides enhanced pathogen 
      resistance
    supporting_text: Mitochondrial UPR-regulated innate immunity provides 
      resistance to pathogen infection.
  - statement: Innate immune genes induced include abf-2, lys-2, clec-4, clec-65
    supporting_text: Mitochondrial UPR-regulated innate immunity provides 
      resistance to pathogen infection.
  - statement: UPRmt can function independent of MAP and c-Jun kinase pathways
    supporting_text: Mitochondrial UPR-regulated innate immunity provides 
      resistance to pathogen infection.
- id: PMID:25773600
  title: Mitochondrial and nuclear accumulation of the transcription factor 
    ATFS-1 promotes OXPHOS recovery during the UPR(mt).
  findings:
  - statement: ATFS-1 binds promoters in both nuclear and mitochondrial genomes
    supporting_text: Mitochondrial and nuclear accumulation of the transcription
      factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).
  - statement: Regulates mitochondrial chaperones, OXPHOS assembly factors, 
      glycolysis genes
    supporting_text: Mitochondrial and nuclear accumulation of the transcription
      factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).
  - statement: Required to limit OXPHOS transcript accumulation during stress
    supporting_text: Mitochondrial and nuclear accumulation of the transcription
      factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).
  - statement: Balanced ATFS-1 accumulation in nucleus and mitochondria promotes
      OXPHOS recovery
    supporting_text: Mitochondrial and nuclear accumulation of the transcription
      factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).
  - statement: Fine-tunes OXPHOS expression to match protein-folding capacity
    supporting_text: Mitochondrial and nuclear accumulation of the transcription
      factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).
- id: PMID:27459203
  title: The Mitochondrial Unfolded Protein Response Protects against Anoxia in 
    Caenorhabditis elegans.
  findings:
  - statement: UPRmt activation protects against anoxia-reperfusion injury
    supporting_text: The Mitochondrial Unfolded Protein Response Protects 
      against Anoxia in Caenorhabditis elegans.
  - statement: atfs-1 is necessary and sufficient for protection
    supporting_text: The Mitochondrial Unfolded Protein Response Protects 
      against Anoxia in Caenorhabditis elegans.
  - statement: atfs-1(et15) gain-of-function mutants are protected from anoxia
    supporting_text: The Mitochondrial Unfolded Protein Response Protects 
      against Anoxia in Caenorhabditis elegans.
  - statement: Protection can be cell-autonomous
    supporting_text: The Mitochondrial Unfolded Protein Response Protects 
      against Anoxia in Caenorhabditis elegans.
- id: PMID:30057120
  title: The Mitochondrial Unfolded Protein Response Is Mediated 
    Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.
  findings:
  - statement: UPRmt can be triggered cell-non-autonomously
    supporting_text: The Mitochondrial Unfolded Protein Response Is Mediated 
      Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.
  - statement: Retromer-dependent Wnt signaling propagates mitochondrial stress 
      signals
    supporting_text: The Mitochondrial Unfolded Protein Response Is Mediated 
      Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.
  - statement: Neuronal mitochondrial stress induces UPRmt in peripheral tissues
    supporting_text: The Mitochondrial Unfolded Protein Response Is Mediated 
      Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.
  - statement: Wnt ligand EGL-20 is sufficient to induce cell-non-autonomous 
      UPRmt
    supporting_text: The Mitochondrial Unfolded Protein Response Is Mediated 
      Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.
- id: PMID:30642431
  title: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated innate 
    immunity and lifespan extension.
  findings:
  - statement: ATFS-1 is SUMOylated at K342
    supporting_text: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated 
      innate immunity and lifespan extension.
  - statement: ULP-4 desumoylates ATFS-1
    supporting_text: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated 
      innate immunity and lifespan extension.
  - statement: Desumoylation enhances ATFS-1 transcriptional activity
    supporting_text: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated 
      innate immunity and lifespan extension.
  - statement: K342R mutation abolishes sumoylation but does not affect nuclear 
      localization
    supporting_text: SUMO peptidase ULP-4 regulates mitochondrial UPR-mediated 
      innate immunity and lifespan extension.
- id: Reactome:R-CEL-9856612
  title: ATFS-1 translocates from the cytosol to the mitochondrial matrix
  findings:
  - statement: Reactome pathway annotation for ATFS-1 mitochondrial import
    supporting_text: In unstressed cells, ATFS-1 is translocated from the 
      cytosol to the mitochondrial matrix where it is constitutively degraded 
      by the protease Lon-P
- id: Reactome:R-CEL-9856623
  title: ATFS-1 translocates from the cytosol to the nucleoplasm
  findings:
  - statement: Reactome pathway annotation for ATFS-1 nuclear translocation 
      during stress
    supporting_text: Upon mitochondrial stress that causes a reduction in 
      mitochondrial import of proteins, less ATFS-1 is imported into 
      mitochondria, ATFS-1 accumulates in the cytosol, and a greater amount of 
      ATFS-1 is imported into the nucleus
- id: file:worm/atfs-1/atfs-1-deep-research-falcon.md
  title: Deep research report on atfs-1
  findings: []
core_functions:
- molecular_function:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase 
      II-specific
  description: ATFS-1 is a bZIP transcription factor that activates expression 
    of UPRmt target genes including mitochondrial chaperones (hsp-6, hsp-60), 
    proteases, OXPHOS assembly factors, metabolic enzymes, and innate immune 
    effectors.
  directly_involved_in:
  - id: GO:0034514
    label: mitochondrial unfolded protein response
  locations:
  - id: GO:0005654
    label: nucleoplasm
- molecular_function:
    id: GO:0034246
    label: mitochondrial transcription factor activity
  description: Uniquely among UPR regulators, ATFS-1 binds and regulates 
    transcription from both nuclear and mitochondrial genomes, coordinating 
    expression of OXPHOS genes encoded by both genomes.
  directly_involved_in:
  - id: GO:0006390
    label: mitochondrial transcription
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
- molecular_function:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase 
      II-specific
  description: ATFS-1 activates innate immune genes during mitochondrial stress 
    and pathogen exposure. UPRmt activation provides resistance to P. aeruginosa
    infection by inducing antimicrobial peptides and lysozymes.
  directly_involved_in:
  - id: GO:0050829
    label: defense response to Gram-negative bacterium
  locations:
  - id: GO:0005654
    label: nucleoplasm
proposed_new_terms: []
suggested_questions:
- question: What is the complete regulon of ATFS-1 target genes?
- question: How do ATFS-1, DVE-1, and UBL-5 cooperate in UPRmt activation?
- question: What determines whether ATFS-1 promotes mitophagy versus UPRmt?
- question: What is the mammalian functional ortholog of ATFS-1?
suggested_experiments:
- description: ChIP-seq in different stress conditions to map the complete 
    ATFS-1 regulon
- description: Structure-function analysis of ATFS-1 domains for nuclear vs 
    mitochondrial function
- description: Single-cell analysis of ATFS-1 localization dynamics during 
    stress
- description: Genetic screens for ATFS-1 cofactors in specific tissue contexts
tags:
- caeel-mitophagy
- caeel-upr-stress