id: P34707
gene_symbol: skn-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: 'SKN-1 is the C. elegans ortholog of mammalian Nrf1/Nrf2 (CNC/bZIP) transcription
  factors, functioning as the master regulator of oxidative stress responses and xenobiotic
  detoxification. SKN-1 has three major isoforms with distinct functions: SKN-1A is
  ER-associated and mediates proteasome stress responses; SKN-1B localizes to ASI
  chemosensory neurons and mediates dietary restriction effects on longevity; SKN-1C
  is the primary intestinal isoform regulating Phase II detoxification genes. SKN-1
  binds DNA as a monomer using a unique mechanism combining a bZIP-like basic region
  with an N-terminal arm for minor groove contacts. Key target genes include glutathione
  S-transferases (gst-4, gst-1), glutamate-cysteine ligase (gcs-1), and proteasome
  subunits. SKN-1 is regulated by p38/PMK-1 phosphorylation (activation), WDR-23/CUL4/DDB1
  ubiquitin ligase complex (degradation), and insulin/IGF-1 signaling via AKT kinases
  (inhibition). Beyond stress responses, SKN-1 plays an essential developmental role
  in mesendoderm specification during embryogenesis, specifying the fate of ventral
  blastomeres that give rise to the pharynx and intestine.'
existing_annotations:
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SKN-1 binds DNA through a unique mechanism involving a bZIP-like 
      basic region combined with an N-terminal arm that contacts the minor 
      groove. Canonical Phase II response element binding is well-established.
    action: ACCEPT
    reason: IBA annotation supported by phylogenetic inference from mammalian 
      Nrf2 orthologs. Crystal structure (PMID:9628487) and extensive biochemical
      studies demonstrate SKN-1 sequence-specific DNA binding to cis-regulatory 
      regions via its basic region and N-terminal arm.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 regulates a key Phase II detoxification gene 
        through constitutive and stress-inducible mechanisms in the ASI 
        chemosensory neurons and intestine, respectively
    - reference_id: PMID:9628487
      supporting_text: A new DNA-binding motif in the Skn-1 binding domain-DNA 
        complex
    - reference_id: file:worm/skn-1/skn-1-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SKN-1 is a well-characterized transcription factor that activates 
      Phase II detoxification genes and developmental target genes through 
      specific binding to promoter regions and recruitment of RNA Pol II 
      machinery.
    action: ACCEPT
    reason: IBA annotation reflects conserved transcription factor function. 
      SKN-1 directly activates transcription of gcs-1, gst-4, and other target 
      genes in response to oxidative stress (PMID:16166371, PMID:12869585). Core
      molecular function of this transcription factor.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: During postembryonic stages, SKN-1 regulates a key Phase 
        II detoxification gene through constitutive and stress-inducible 
        mechanisms in the ASI chemosensory neurons and intestine, respectively
    - reference_id: PMID:16166371
      supporting_text: In response to oxidative stress, PMK-1 phosphorylates 
        SKN-1, leading to its accumulation in intestine nuclei, where SKN-1 
        activates transcription of gcs-1, a phase II detoxification enzyme gene
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SKN-1 translocates to the nucleus upon oxidative stress to activate
      target gene transcription. Nuclear localization is dynamically regulated 
      by p38/PMK-1 phosphorylation.
    action: ACCEPT
    reason: Core cellular component annotation. Nuclear localization is 
      dynamically regulated and essential for SKN-1 transcriptional activity. 
      Basally present in ASI neuron nuclei, stress-inducible in intestinal 
      nuclei.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 is present in ASI nuclei under normal conditions, 
        and accumulates in intestinal nuclei in response to oxidative stress
    - reference_id: PMID:16166371
      supporting_text: PMK-1 p38 MAPK pathway regulates the oxidative stress 
        response via the CNC transcription factor SKN-1
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: SKN-1 regulates transcription of multiple target genes through RNA 
      polymerase II, including Phase II detoxification genes and developmental 
      markers.
    action: ACCEPT
    reason: IBA annotation supported by extensive experimental evidence. SKN-1 
      is a master transcriptional regulator of stress response and developmental
      programs. Binding to promoters directly activates target gene expression.
    supported_by:
    - reference_id: PMID:16166371
      supporting_text: SKN-1 activates transcription of gcs-1, a phase II 
        detoxification enzyme gene
    - reference_id: PMID:12869585
      supporting_text: SKN-1 links C. elegans mesendodermal specification to a 
        conserved oxidative stress response
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation based on InterPro domain mapping for NFE2-like 
      domain (IPR047167), which characterizes bZIP-like transcription factors.
    action: ACCEPT
    reason: InterPro-based annotation is accurate given SKN-1's characterized 
      DNA-binding domain and experimental validation of sequence-specific 
      binding through crystal structure analysis.
    additional_reference_ids:
    - PMID:9628487
    supported_by:
    - reference_id: PMID:9628487
      supporting_text: A new DNA-binding motif in the Skn-1 binding domain-DNA 
        complex.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: General DNA binding annotation based on combined automated methods.
    action: ACCEPT
    reason: Accurate but general annotation. More specific DNA-binding terms are
      also annotated.
- 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 mappings.
    action: ACCEPT
    reason: Accurate annotation consistent with SKN-1's established function as 
      a transcription factor.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation from UniProt subcellular location mapping.
    action: ACCEPT
    reason: Duplicates the IBA and IDA annotations but provides additional 
      automated evidence support.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SKN-1 localizes to cytoplasm under basal conditions and 
      translocates to nucleus upon stress activation.
    action: ACCEPT
    reason: Accurate annotation. Cytoplasmic localization under non-stress 
      conditions is well-documented.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: SKN-1 isoform A has been shown to localize to mitochondria.
    action: ACCEPT
    reason: Mitochondrial localization is specific to SKN-1A isoform and has 
      been experimentally validated (PMID:23040073).
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: General transcription annotation from UniProt keyword mapping.
    action: ACCEPT
    reason: Accurate but general. More specific transcription regulatory terms 
      are also present.
- 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 domain mapping.
    action: ACCEPT
    reason: Accurate annotation. SKN-1 regulates transcription of stress 
      response and developmental genes.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation from InterPro NFE2-like domain.
    action: ACCEPT
    reason: Accurate annotation consistent with SKN-1's established function in 
      RNA polymerase II-dependent transcription.
- term:
    id: GO:0006417
    label: regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation from UniProt keyword mapping. Evidence for SKN-1 
      directly regulating translation is limited.
    action: REMOVE
    reason: This IEA annotation (from UniProt keyword KW-0810) is an over-annotation
      and should be removed. SKN-1 is a bZIP/CNC-family transcription factor that lacks
      any recognized RNA-binding or translation-factor domain, and its only established
      regulatory activity is transcriptional (RNA polymerase II target genes). An
      OpenScientist run testing this annotation found that the keyword most likely
      conflates SKN-1 being activated by translation inhibition (acting as a downstream
      transcriptional effector) with SKN-1 directly regulating translation; no
      experimental evidence supports a direct translational role.
    supported_by:
    - reference_id: file:worm/skn-1/skn-1-hypotheses/translation-regulation-overannotation/openscientist.md
      supporting_text: the protein lacks all recognized RNA-binding and translation-factor
        domains.
    - reference_id: file:worm/skn-1/skn-1-hypotheses/translation-regulation-overannotation/openscientist.md
      supporting_text: The curation recommendation is to remove GO:0006417 from P34707
        and to flag UniProtKB keyword KW-0810 for removal from this entry.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ARBA machine learning annotation for regulation of gene expression.
    action: ACCEPT
    reason: Accurate but general annotation. SKN-1 regulates expression of Phase
      II detoxification genes.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:24068940
  review:
    summary: SKN-1 positively regulates transcription of Phase II detoxification
      genes in response to oxidative and ER stress.
    action: ACCEPT
    reason: Core molecular function annotation. SKN-1 is a transcriptional 
      activator of stress response genes.
    supported_by:
    - reference_id: PMID:24068940
      supporting_text: Sep 12. Integration of the unfolded protein and oxidative
        stress responses through SKN-1/Nrf.
- term:
    id: GO:1990748
    label: cellular detoxification
  evidence_type: IMP
  original_reference_id: PMID:23721876
  review:
    summary: SKN-1 regulates expression of glutathione S-transferases and other 
      Phase II detoxification enzymes.
    action: ACCEPT
    reason: Core biological process annotation. SKN-1/Nrf2 is the master 
      regulator of cellular detoxification responses.
    supported_by:
    - reference_id: PMID:23721876
      supporting_text: GST-1-mediated neuroprotection is dependent on the 
        PD-associated transcription factor Nrf2/SKN-1, as a reduction in SKN-1 
        gene expression results in a decrease in GST-1 protein expression
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:28600327
  review:
    summary: Direct demonstration of SKN-1 DNA binding in the context of 
      oxidative stress response.
    action: ACCEPT
    reason: IDA evidence confirms SKN-1 binds specifically to cis-regulatory 
      regions of target genes.
    supported_by:
    - reference_id: PMID:28600327
      supporting_text: 2017 Jun 9. The Oxidative Stress Response in 
        Caenorhabditis elegans Requires the GATA Transcription Factor ELT-3 and 
        SKN-1/Nrf2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28600327
  review:
    summary: SKN-1 interacts with ELT-3 (GATA transcription factor) to 
      co-activate target gene transcription.
    action: MODIFY
    reason: Protein binding is too general. SKN-1 has specific protein 
      interactions with transcriptional regulators like ELT-3.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:28600327
      supporting_text: 2017 Jun 9. The Oxidative Stress Response in 
        Caenorhabditis elegans Requires the GATA Transcription Factor ELT-3 and 
        SKN-1/Nrf2.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:28600327
  review:
    summary: IDA evidence for nuclear localization of SKN-1 isoforms B and C 
      during oxidative stress response.
    action: ACCEPT
    reason: Consistent with other nuclear localization annotations.
    supported_by:
    - reference_id: PMID:28600327
      supporting_text: 2017 Jun 9. The Oxidative Stress Response in 
        Caenorhabditis elegans Requires the GATA Transcription Factor ELT-3 and 
        SKN-1/Nrf2.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:28600327
  review:
    summary: SKN-1 activity extends lifespan in C. elegans.
    action: ACCEPT
    reason: Core biological process annotation. SKN-1's role in longevity is 
      well-established.
    supported_by:
    - reference_id: PMID:28600327
      supporting_text: 2017 Jun 9. The Oxidative Stress Response in 
        Caenorhabditis elegans Requires the GATA Transcription Factor ELT-3 and 
        SKN-1/Nrf2.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:28600327
  review:
    summary: SKN-1 positively regulates transcription of gst-4 and other Phase 
      II detoxification genes.
    action: ACCEPT
    reason: Valid experimental evidence for this core function.
    supported_by:
    - reference_id: PMID:28600327
      supporting_text: 2017 Jun 9. The Oxidative Stress Response in 
        Caenorhabditis elegans Requires the GATA Transcription Factor ELT-3 and 
        SKN-1/Nrf2.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:34407394
  review:
    summary: Nuclear localization of SKN-1 demonstrated in context of innate 
      immunity responses.
    action: ACCEPT
    reason: Confirms nuclear localization during pathogen infection.
    supported_by:
    - reference_id: PMID:34407394
      supporting_text: Tribbles pseudokinase NIPI-3 regulates intestinal 
        immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity.
- term:
    id: GO:0042742
    label: defense response to bacterium
  evidence_type: IMP
  original_reference_id: PMID:34407394
  review:
    summary: SKN-1 is required for intestinal defense against bacterial 
      pathogens.
    action: ACCEPT
    reason: Important biological process annotation. SKN-1 integrates oxidative 
      stress and innate immunity responses.
    supported_by:
    - reference_id: PMID:34407394
      supporting_text: Tribbles pseudokinase NIPI-3 regulates intestinal 
        immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity.
- term:
    id: GO:0048565
    label: digestive tract development
  evidence_type: IMP
  original_reference_id: PMID:1547503
  review:
    summary: SKN-1 is required for specification of mesendoderm during 
      embryogenesis, which gives rise to pharynx and intestine.
    action: ACCEPT
    reason: Core developmental function annotation.
    supported_by:
    - reference_id: PMID:1547503
      supporting_text: skn-1, a maternally expressed gene required to specify 
        the fate of ventral blastomeres in the early C.
- term:
    id: GO:0048566
    label: embryonic digestive tract development
  evidence_type: IMP
  original_reference_id: PMID:1547503
  review:
    summary: More specific annotation for SKN-1's role in embryonic gut 
      development.
    action: ACCEPT
    reason: Appropriately specific developmental annotation.
    supported_by:
    - reference_id: PMID:1547503
      supporting_text: skn-1, a maternally expressed gene required to specify 
        the fate of ventral blastomeres in the early C.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:26016853
  review:
    summary: SKN-1 regulates expression of innate immunity genes in the adult 
      intestine.
    action: ACCEPT
    reason: General annotation but accurate.
    supported_by:
    - reference_id: PMID:26016853
      supporting_text: SKN-1/Nrf, better known for regulating oxidative stress 
        responses, was further found to contribute to resistance against 
        bacterial pathogens
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IMP
  original_reference_id: PMID:26016853
  review:
    summary: SKN-1 contributes to defense against Gram-negative bacteria like P.
      aeruginosa.
    action: ACCEPT
    reason: Specific innate immunity annotation supported by experimental 
      evidence.
    supported_by:
    - reference_id: PMID:26016853
      supporting_text: SKN-1/Nrf, better known for regulating oxidative stress 
        responses, was further found to contribute to resistance against 
        bacterial pathogens
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific 
      DNA binding
  evidence_type: IDA
  original_reference_id: PMID:24068940
  review:
    summary: Direct demonstration of SKN-1 binding to regulatory regions of 
      target genes.
    action: ACCEPT
    reason: IDA evidence for specific DNA binding to transcription regulatory 
      regions.
    supported_by:
    - reference_id: PMID:24068940
      supporting_text: Sep 12. Integration of the unfolded protein and oxidative
        stress responses through SKN-1/Nrf.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:12869585
  review:
    summary: Seminal paper demonstrating SKN-1 activates Phase II detoxification
      genes in response to oxidative stress.
    action: ACCEPT
    reason: Key publication establishing SKN-1's role as transcriptional 
      activator.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 regulates a key Phase II detoxification gene 
        through constitutive and stress-inducible mechanisms in the ASI 
        chemosensory neurons and intestine, respectively
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:25688864
  review:
    summary: SKN-1 positively regulates transcription of riok-1 in the 
      intestine.
    action: ACCEPT
    reason: Additional experimental evidence for SKN-1's transcriptional 
      activator function.
    supported_by:
    - reference_id: PMID:25688864
      supporting_text: eCollection 2015. Investigating the role of RIO protein 
        kinases in Caenorhabditis elegans.
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific 
      DNA binding
  evidence_type: IDA
  original_reference_id: PMID:12869585
  review:
    summary: Direct demonstration of SKN-1 binding to gcs-1 regulatory region.
    action: ACCEPT
    reason: IDA evidence from seminal paper on SKN-1 function.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 is present in ASI nuclei under normal conditions, 
        and accumulates in intestinal nuclei in response to oxidative stress
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific 
      DNA binding
  evidence_type: IDA
  original_reference_id: PMID:24453991
  review:
    summary: SKN-1 binds to regulatory regions of nlg-1/neuroligin to regulate 
      its expression.
    action: ACCEPT
    reason: IDA evidence for SKN-1 DNA binding with a novel target gene.
    supported_by:
    - reference_id: PMID:24453991
      supporting_text: 2014 Jan 16. Regulation of synaptic nlg-1/neuroligin 
        abundance by the skn-1/Nrf stress response pathway protects against 
        oxidative stress.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IPI
  original_reference_id: PMID:24068940
  review:
    summary: SKN-1 interacts with Hsp70 family members (hsp-4) during 
      integration of ER stress and oxidative stress responses.
    action: ACCEPT
    reason: Specific protein interaction annotation. HSP-4 interaction is 
      relevant to SKN-1A's role in ER/proteasome stress responses.
    supported_by:
    - reference_id: PMID:24068940
      supporting_text: Sep 12. Integration of the unfolded protein and oxidative
        stress responses through SKN-1/Nrf.
- term:
    id: GO:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: IEP
  original_reference_id: PMID:24068940
  review:
    summary: SKN-1 expression/activity is modulated by IRE1 branch of UPR.
    action: KEEP_AS_NON_CORE
    reason: SKN-1 participates in UPR but this represents an integration point 
      rather than core function.
    supported_by:
    - reference_id: PMID:24068940
      supporting_text: Sep 12. Integration of the unfolded protein and oxidative
        stress responses through SKN-1/Nrf.
- term:
    id: GO:0036500
    label: ATF6-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:26232625
  review:
    summary: SKN-1 integrates with ATF6 branch of UPR based on review of stress 
      response integration.
    action: KEEP_AS_NON_CORE
    reason: Represents integration of stress pathways rather than core SKN-1 
      function.
    supported_by:
    - reference_id: PMID:26232625
      supporting_text: SKN-1/Nrf, stress responses, and aging in Caenorhabditis 
        elegans.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23721876
  review:
    summary: SKN-1 positively regulates expression of GST-1 and other 
      detoxification genes.
    action: ACCEPT
    reason: Accurate annotation. SKN-1 activates expression of Phase II 
      detoxification genes.
    supported_by:
    - reference_id: PMID:23721876
      supporting_text: a reduction in SKN-1 gene expression results in a 
        decrease in GST-1 protein expression
- term:
    id: GO:1905804
    label: positive regulation of cellular response to manganese ion
  evidence_type: IMP
  original_reference_id: PMID:23721876
  review:
    summary: SKN-1 protects against manganese toxicity by activating 
      detoxification genes.
    action: KEEP_AS_NON_CORE
    reason: This represents a specific application of SKN-1's general 
      detoxification function.
    supported_by:
    - reference_id: PMID:23721876
      supporting_text: a Caenorhabditis elegans GSTpi homologue, GST-1, inhibits
        Mn-induced DA neuron degeneration
- term:
    id: GO:1905804
    label: positive regulation of cellular response to manganese ion
  evidence_type: IGI
  original_reference_id: PMID:23721876
  review:
    summary: Genetic interaction evidence for SKN-1's role in manganese 
      response.
    action: KEEP_AS_NON_CORE
    reason: Same term with different evidence code. Represents specific stress 
      context.
    supported_by:
    - reference_id: PMID:23721876
      supporting_text: 2013 May 27. The Nrf2/SKN-1-dependent glutathione 
        S-transferase π homologue GST-1 inhibits dopamine neuron degeneration in
        a Caenorhabditis elegans model of manganism.
- term:
    id: GO:1901562
    label: response to paraquat
  evidence_type: IGI
  original_reference_id: PMID:19783783
  review:
    summary: SKN-1 is required for response to paraquat-induced oxidative 
      stress.
    action: KEEP_AS_NON_CORE
    reason: Paraquat is a specific oxidative stressor. The core function is 
      response to oxidative stress more generally.
    supported_by:
    - reference_id: PMID:19783783
      supporting_text: Life-span extension by dietary restriction is mediated by
        NLP-7 signaling and coelomocyte endocytosis in C.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:19783783
  review:
    summary: Genetic interaction evidence for SKN-1 in lifespan determination, 
      specifically in context of dietary restriction.
    action: ACCEPT
    reason: Core biological process. SKN-1 promotes longevity through multiple 
      mechanisms.
    supported_by:
    - reference_id: PMID:19783783
      supporting_text: Life-span extension by dietary restriction is mediated by
        NLP-7 signaling and coelomocyte endocytosis in C.
- term:
    id: GO:0048566
    label: embryonic digestive tract development
  evidence_type: IGI
  original_reference_id: PMID:25819561
  review:
    summary: Genetic interaction demonstrating SKN-1's role in embryonic gut 
      specification.
    action: ACCEPT
    reason: Core developmental function. Maternal SKN-1 specifies mesendoderm 
      fate.
    supported_by:
    - reference_id: PMID:25819561
      supporting_text: 2015 Mar 26. Centrosome-Associated Degradation Limits 
        β-Catenin Inheritance by Daughter Cells after Asymmetric Division.
- term:
    id: GO:0001714
    label: endodermal cell fate specification
  evidence_type: IMP
  original_reference_id: PMID:25819561
  review:
    summary: SKN-1 specifies endodermal cell fates through activation of 
      downstream transcription factors.
    action: ACCEPT
    reason: Core developmental function. SKN-1 activates MED-1/2 which in turn 
      activate END-1/3 for endoderm specification.
    supported_by:
    - reference_id: PMID:25819561
      supporting_text: 2015 Mar 26. Centrosome-Associated Degradation Limits 
        β-Catenin Inheritance by Daughter Cells after Asymmetric Division.
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:9303538
  review:
    summary: Biochemical demonstration of SKN-1's sequence-specific DNA binding 
      through its unique Skn domain.
    action: ACCEPT
    reason: Core molecular function. SKN-1 binds DNA as a monomer through a 
      unique mechanism.
    supported_by:
    - reference_id: PMID:9303538
      supporting_text: SKN-1 domain folding and basic region monomer 
        stabilization upon DNA binding.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:24068940
  review:
    summary: SKN-1A isoform localizes to the ER via N-terminal transmembrane 
      domain.
    action: ACCEPT
    reason: Accurate isoform-specific localization. SKN-1A is ER-associated.
    supported_by:
    - reference_id: PMID:24068940
      supporting_text: Sep 12. Integration of the unfolded protein and oxidative
        stress responses through SKN-1/Nrf.
- term:
    id: GO:0000303
    label: response to superoxide
  evidence_type: IEP
  original_reference_id: PMID:12869585
  review:
    summary: SKN-1 expression/activity is induced by superoxide/oxidative 
      stress.
    action: ACCEPT
    reason: Core stress response function. SKN-1 is activated by and protects 
      against oxidative stress.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: skn-1 mutants are sensitive to oxidative stress and have 
        shortened lifespans
- term:
    id: GO:0000303
    label: response to superoxide
  evidence_type: IMP
  original_reference_id: PMID:12869585
  review:
    summary: SKN-1 is required for proper response to superoxide stress.
    action: ACCEPT
    reason: IMP evidence for same term. Both evidence codes are appropriate.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 links C. elegans mesendodermal specification to a 
        conserved oxidative stress response.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12869585
  review:
    summary: Nuclear localization of SKN-1 in ASI neurons and intestinal cells 
      during stress response.
    action: ACCEPT
    reason: Key publication demonstrating stress-induced nuclear translocation.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 is present in ASI nuclei under normal conditions, 
        and accumulates in intestinal nuclei in response to oxidative stress
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IEP
  original_reference_id: PMID:12869585
  review:
    summary: SKN-1 expression/activity is induced by oxidative stress.
    action: ACCEPT
    reason: Core biological process annotation. SKN-1 is the master regulator of
      oxidative stress responses in C. elegans.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 functions similarly to resist oxidative stress in 
        C. elegans
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:12869585
  review:
    summary: SKN-1 mutants have shortened lifespan, demonstrating its role in 
      longevity.
    action: ACCEPT
    reason: Core phenotype. SKN-1 promotes longevity through stress resistance.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: skn-1 mutants are sensitive to oxidative stress and have 
        shortened lifespans
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: IEP
  original_reference_id: PMID:12869585
  review:
    summary: SKN-1 activity is induced by heat stress.
    action: KEEP_AS_NON_CORE
    reason: Heat stress response is one of many stress contexts where SKN-1 is 
      activated, but oxidative stress response is the core function.
    supported_by:
    - reference_id: PMID:12869585
      supporting_text: SKN-1 links C. elegans mesendodermal specification to a 
        conserved oxidative stress response.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:23040073
  review:
    summary: SKN-1A isoform localizes to mitochondria where it interacts with 
      PGAM-5.
    action: ACCEPT
    reason: Isoform-specific localization with functional significance for 
      metabolic stress responses.
    supported_by:
    - reference_id: PMID:23040073
      supporting_text: Mitochondrial SKN-1/Nrf mediates a conserved starvation 
        response.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16166371
  review:
    summary: Nuclear localization demonstrated in context of p38 MAPK 
      regulation.
    action: ACCEPT
    reason: Key publication showing PMK-1-dependent nuclear translocation.
    supported_by:
    - reference_id: PMID:16166371
      supporting_text: In response to oxidative stress, PMK-1 phosphorylates 
        SKN-1, leading to its accumulation in intestine nuclei
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:22560223
  review:
    summary: SKN-1 mediates lifespan extension by rapamycin and reduced TOR 
      signaling.
    action: ACCEPT
    reason: Core longevity function. SKN-1 is required for lifespan extension in
      multiple genetic and pharmacological contexts.
    supported_by:
    - reference_id: PMID:22560223
      supporting_text: TOR signaling and rapamycin influence longevity by 
        regulating SKN-1/Nrf and DAF-16/FoxO.
- term:
    id: GO:1900409
    label: positive regulation of cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:22560223
  review:
    summary: SKN-1 positively regulates oxidative stress responses downstream of
      TOR signaling.
    action: ACCEPT
    reason: Core function. SKN-1 activates protective stress response programs.
    supported_by:
    - reference_id: PMID:22560223
      supporting_text: TOR signaling and rapamycin influence longevity by 
        regulating SKN-1/Nrf and DAF-16/FoxO.
- term:
    id: GO:0048382
    label: mesendoderm development
  evidence_type: IMP
  original_reference_id: PMID:1547503
  review:
    summary: SKN-1 is required for mesendoderm specification in early 
      embryogenesis.
    action: ACCEPT
    reason: Core developmental function. This is the original embryonic function
      described for SKN-1.
    supported_by:
    - reference_id: PMID:1547503
      supporting_text: skn-1, a maternally expressed gene required to specify 
        the fate of ventral blastomeres in the early C.
- term:
    id: GO:0001714
    label: endodermal cell fate specification
  evidence_type: IGI
  original_reference_id: PMID:15979606
  review:
    summary: Genetic interactions with end-1 and end-3 for endoderm 
      specification.
    action: ACCEPT
    reason: Core developmental function. SKN-1 acts upstream of END-1/3 GATA 
      factors.
    supported_by:
    - reference_id: PMID:15979606
      supporting_text: Genetic redundancy in endoderm specification within the 
        genus Caenorhabditis.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:20523893
  review:
    summary: Genetic interaction evidence for SKN-1 in lifespan regulation.
    action: ACCEPT
    reason: Additional genetic evidence for core longevity function.
    supported_by:
    - reference_id: PMID:20523893
      supporting_text: Manipulation of behavioral decline in Caenorhabditis 
        elegans with the Rag GTPase raga-1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19273594
  review:
    summary: SKN-1 interacts with WDR-23, the adaptor for CUL4/DDB1 ubiquitin 
      ligase that targets SKN-1 for degradation.
    action: MODIFY
    reason: Protein binding is too general. WDR-23 is a specific regulatory 
      interaction.
    proposed_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:19273594
      supporting_text: Mar 9. The WD40 repeat protein WDR-23 functions with the 
        CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of
        SKN-1 in Caenorhabditis elegans.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:18358814
  review:
    summary: SKN-1 promotes longevity when insulin-like signaling is reduced or 
      when SKN-1 is constitutively active.
    action: ACCEPT
    reason: Seminal paper demonstrating SKN-1's role in longevity downstream of 
      insulin/IGF-1 signaling.
    supported_by:
    - reference_id: PMID:18358814
      supporting_text: Direct inhibition of the longevity-promoting factor SKN-1
        by insulin-like signaling in C.
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:9628487
  review:
    summary: Crystal structure demonstrates SKN-1's unique DNA-binding 
      mechanism.
    action: ACCEPT
    reason: Structural evidence for DNA binding mechanism.
    supported_by:
    - reference_id: PMID:9628487
      supporting_text: A new DNA-binding motif in the Skn-1 binding domain-DNA 
        complex.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:8348611
  review:
    summary: Early demonstration of SKN-1 nuclear localization in embryos.
    action: ACCEPT
    reason: Original publication on SKN-1 protein localization.
    supported_by:
    - reference_id: PMID:8348611
      supporting_text: The maternal gene skn-1 encodes a protein that is 
        distributed unequally in early C.
- term:
    id: GO:0001708
    label: cell fate specification
  evidence_type: IMP
  original_reference_id: PMID:8861906
  review:
    summary: SKN-1 specifies cell fates during early embryonic patterning.
    action: ACCEPT
    reason: Core developmental function.
    supported_by:
    - reference_id: PMID:8861906
      supporting_text: Spatial and temporal controls target pal-1 
        blastomere-specification activity to a single blastomere lineage in C.
- term:
    id: GO:0009880
    label: embryonic pattern specification
  evidence_type: IMP
  original_reference_id: PMID:8861906
  review:
    summary: SKN-1 contributes to embryonic pattern specification along with 
      PAL-1.
    action: ACCEPT
    reason: Core developmental function. SKN-1 is part of the maternal gene 
      network that patterns the early embryo.
    supported_by:
    - reference_id: PMID:8861906
      supporting_text: Spatial and temporal controls target pal-1 
        blastomere-specification activity to a single blastomere lineage in C.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: NAS
  original_reference_id: PMID:1547503
  review:
    summary: Original publication identifying SKN-1 as transcription factor.
    action: ACCEPT
    reason: NAS from original discovery paper. Later confirmed by extensive 
      experimental evidence.
    supported_by:
    - reference_id: PMID:1547503
      supporting_text: skn-1, a maternally expressed gene required to specify 
        the fate of ventral blastomeres in the early C.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1547503
  title: skn-1, a maternally expressed gene required to specify the fate of 
    ventral blastomeres in the early C. elegans embryo.
  findings:
  - statement: SKN-1 is required for mesendoderm specification
    supporting_text: skn-1, a maternally expressed gene required to specify the 
      fate of ventral blastomeres in the early C. elegans embryo.
  - statement: SKN-1 specifies fate of ventral blastomeres
    supporting_text: skn-1, a maternally expressed gene required to specify the 
      fate of ventral blastomeres in the early C. elegans embryo.
  - statement: Maternal contribution is essential for gut development
    supporting_text: skn-1, a maternally expressed gene required to specify the 
      fate of ventral blastomeres in the early C. elegans embryo.
- id: PMID:8348611
  title: The maternal gene skn-1 encodes a protein that is distributed unequally
    in early C. elegans embryos.
  findings:
  - statement: SKN-1 protein localization in early embryos
    supporting_text: The maternal gene skn-1 encodes a protein that is 
      distributed unequally in early C. elegans embryos.
- id: PMID:8861906
  title: Spatial and temporal controls target pal-1 blastomere-specification 
    activity to a single blastomere lineage in C. elegans embryos.
  findings:
  - statement: SKN-1 and PAL-1 function in embryonic patterning
    supporting_text: Spatial and temporal controls target pal-1 
      blastomere-specification activity to a single blastomere lineage in C. 
      elegans embryos.
- id: PMID:9303538
  title: SKN-1 domain folding and basic region monomer stabilization upon DNA 
    binding.
  findings:
  - statement: SKN-1 binds DNA as a monomer through unique mechanism
    supporting_text: SKN-1 domain folding and basic region monomer stabilization
      upon DNA binding.
  - statement: Skn domain structure and DNA-binding properties characterized
    supporting_text: SKN-1 domain folding and basic region monomer stabilization
      upon DNA binding.
- id: PMID:9628487
  title: A new DNA-binding motif in the Skn-1 binding domain-DNA complex.
  findings:
  - statement: Crystal structure of SKN-1 DNA-binding domain
    supporting_text: A new DNA-binding motif in the Skn-1 binding domain-DNA 
      complex.
  - statement: Novel fold with four-helix unit organizing DNA contacts
    supporting_text: A new DNA-binding motif in the Skn-1 binding domain-DNA 
      complex.
- id: PMID:12869585
  title: SKN-1 links C. elegans mesendodermal specification to a conserved 
    oxidative stress response.
  findings:
  - statement: SKN-1 regulates Phase II detoxification genes
    supporting_text: SKN-1 links C. elegans mesendodermal specification to a 
      conserved oxidative stress response.
  - statement: SKN-1 accumulates in intestinal nuclei upon oxidative stress
    supporting_text: SKN-1 links C. elegans mesendodermal specification to a 
      conserved oxidative stress response.
  - statement: skn-1 mutants are sensitive to oxidative stress
    supporting_text: SKN-1 links C. elegans mesendodermal specification to a 
      conserved oxidative stress response.
  - statement: skn-1 mutants have shortened lifespan
    supporting_text: SKN-1 links C. elegans mesendodermal specification to a 
      conserved oxidative stress response.
- id: PMID:15979606
  title: Genetic redundancy in endoderm specification within the genus 
    Caenorhabditis.
  findings:
  - statement: SKN-1 activates end-1 and end-3 for endoderm specification
    supporting_text: Genetic redundancy in endoderm specification within the 
      genus Caenorhabditis.
- id: PMID:16166371
  title: The C. elegans p38 MAPK pathway regulates nuclear localization of the 
    transcription factor SKN-1 in oxidative stress response.
  findings:
  - statement: PMK-1 phosphorylates SKN-1 at Ser-164 and Ser-430
    supporting_text: The C. elegans p38 MAPK pathway regulates nuclear 
      localization of the transcription factor SKN-1 in oxidative stress 
      response.
  - statement: Phosphorylation promotes nuclear localization
    supporting_text: The C. elegans p38 MAPK pathway regulates nuclear 
      localization of the transcription factor SKN-1 in oxidative stress 
      response.
  - statement: SKN-1 activates gcs-1 transcription
    supporting_text: The C. elegans p38 MAPK pathway regulates nuclear 
      localization of the transcription factor SKN-1 in oxidative stress 
      response.
- id: PMID:18358814
  title: Direct inhibition of the longevity-promoting factor SKN-1 by 
    insulin-like signaling in C. elegans.
  findings:
  - statement: IIS kinases AKT-1/2 and SGK-1 phosphorylate SKN-1
    supporting_text: Direct inhibition of the longevity-promoting factor SKN-1 
      by insulin-like signaling in C. elegans.
  - statement: Reduced IIS leads to SKN-1 nuclear accumulation
    supporting_text: Direct inhibition of the longevity-promoting factor SKN-1 
      by insulin-like signaling in C. elegans.
  - statement: SKN-1 promotes longevity independently of DAF-16
    supporting_text: Direct inhibition of the longevity-promoting factor SKN-1 
      by insulin-like signaling in C. elegans.
- id: PMID:19273594
  title: The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin 
    ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis
    elegans.
  findings:
  - statement: WDR-23 targets SKN-1 for proteasomal degradation
    supporting_text: The WD40 repeat protein WDR-23 functions with the CUL4/DDB1
      ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in 
      Caenorhabditis elegans.
  - statement: CUL4/DDB1 ubiquitin ligase complex controls SKN-1 levels
    supporting_text: The WD40 repeat protein WDR-23 functions with the CUL4/DDB1
      ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in 
      Caenorhabditis elegans.
- id: PMID:19783783
  title: Life-span extension by dietary restriction is mediated by NLP-7 
    signaling and coelomocyte endocytosis in C. elegans.
  findings:
  - statement: SKN-1 involved in dietary restriction-mediated lifespan extension
    supporting_text: Life-span extension by dietary restriction is mediated by 
      NLP-7 signaling and coelomocyte endocytosis in C. elegans.
- id: PMID:20523893
  title: Manipulation of behavioral decline in Caenorhabditis elegans with the 
    Rag GTPase raga-1.
  findings:
  - statement: Genetic interactions with SKN-1 in lifespan regulation
    supporting_text: Manipulation of behavioral decline in Caenorhabditis 
      elegans with the Rag GTPase raga-1.
- id: PMID:22560223
  title: TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf
    and DAF-16/FoxO.
  findings:
  - statement: TORC1 inhibition activates SKN-1
    supporting_text: TOR signaling and rapamycin influence longevity by 
      regulating SKN-1/Nrf and DAF-16/FoxO.
  - statement: SKN-1 required for rapamycin-mediated lifespan extension
    supporting_text: TOR signaling and rapamycin influence longevity by 
      regulating SKN-1/Nrf and DAF-16/FoxO.
  - statement: SKN-1 and DAF-16 have non-overlapping functions
    supporting_text: TOR signaling and rapamycin influence longevity by 
      regulating SKN-1/Nrf and DAF-16/FoxO.
- id: PMID:23040073
  title: Mitochondrial SKN-1/Nrf mediates a conserved starvation response.
  findings:
  - statement: SKN-1 interacts with PGAM-5 and MXL-3
    supporting_text: Mitochondrial SKN-1/Nrf mediates a conserved starvation 
      response.
  - statement: SKN-1 mediates metabolic adaptation to starvation
    supporting_text: Mitochondrial SKN-1/Nrf mediates a conserved starvation 
      response.
  - statement: Mitochondrial localization of SKN-1 isoform
    supporting_text: Mitochondrial SKN-1/Nrf mediates a conserved starvation 
      response.
- id: PMID:23721876
  title: "The Nrf2/SKN-1-dependent glutathione S-transferase π homologue GST-1 inhibits
    dopamine neuron degeneration in a Caenorhabditis elegans model of manganism."
  findings:
  - statement: SKN-1 regulates GST-1 expression
    supporting_text: The Nrf2/SKN-1-dependent glutathione S-transferase π 
      homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis 
      elegans model of manganism.
  - statement: SKN-1 protects against manganese toxicity
    supporting_text: The Nrf2/SKN-1-dependent glutathione S-transferase π 
      homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis 
      elegans model of manganism.
  - statement: Phase II detoxification is neuroprotective
    supporting_text: The Nrf2/SKN-1-dependent glutathione S-transferase π 
      homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis 
      elegans model of manganism.
- id: PMID:24068940
  title: Integration of the unfolded protein and oxidative stress responses 
    through SKN-1/Nrf.
  findings:
  - statement: SKN-1 integrates UPR and oxidative stress responses
    supporting_text: Integration of the unfolded protein and oxidative stress 
      responses through SKN-1/Nrf.
  - statement: SKN-1 interacts with Hsp70/HSP-4
    supporting_text: Integration of the unfolded protein and oxidative stress 
      responses through SKN-1/Nrf.
  - statement: ER localization of SKN-1A
    supporting_text: Integration of the unfolded protein and oxidative stress 
      responses through SKN-1/Nrf.
- id: PMID:24453991
  title: Regulation of synaptic nlg-1/neuroligin abundance by the skn-1/Nrf 
    stress response pathway protects against oxidative stress.
  findings:
  - statement: SKN-1 regulates nlg-1 expression
    supporting_text: Regulation of synaptic nlg-1/neuroligin abundance by the 
      skn-1/Nrf stress response pathway protects against oxidative stress.
- id: PMID:25688864
  title: Investigating the role of RIO protein kinases in Caenorhabditis 
    elegans.
  findings:
  - statement: SKN-1 regulates riok-1 expression
    supporting_text: Investigating the role of RIO protein kinases in 
      Caenorhabditis elegans.
- id: PMID:25819561
  title: "Centrosome-Associated Degradation Limits β-Catenin Inheritance by Daughter
    Cells after Asymmetric Division."
  findings:
  - statement: SKN-1 role in endodermal cell fate specification
    supporting_text: Centrosome-Associated Degradation Limits β-Catenin 
      Inheritance by Daughter Cells after Asymmetric Division.
- id: PMID:26016853
  title: The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent 
    Immune Responses in Adult C. elegans.
  findings:
  - statement: SKN-1 regulates innate immunity genes
    supporting_text: The Developmental Intestinal Regulator ELT-2 Controls 
      p38-Dependent Immune Responses in Adult C. elegans.
  - statement: Defense response to Gram-negative bacteria
    supporting_text: The Developmental Intestinal Regulator ELT-2 Controls 
      p38-Dependent Immune Responses in Adult C. elegans.
- id: PMID:26232625
  title: SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans.
  findings:
  - statement: Comprehensive review of SKN-1 functions
    supporting_text: SKN-1/Nrf, stress responses, and aging in Caenorhabditis 
      elegans.
  - statement: SKN-1 regulates stress responses, metabolism, and aging
    supporting_text: SKN-1/Nrf, stress responses, and aging in Caenorhabditis 
      elegans.
  - statement: Complex regulation by multiple signaling pathways
    supporting_text: SKN-1/Nrf, stress responses, and aging in Caenorhabditis 
      elegans.
- id: PMID:28600327
  title: The Oxidative Stress Response in Caenorhabditis elegans Requires the 
    GATA Transcription Factor ELT-3 and SKN-1/Nrf2.
  findings:
  - statement: SKN-1 interacts with ELT-3 to activate gst-4
    supporting_text: The Oxidative Stress Response in Caenorhabditis elegans 
      Requires the GATA Transcription Factor ELT-3 and SKN-1/Nrf2.
  - statement: BRAP-2 negatively regulates SKN-1 through p38 inhibition
    supporting_text: The Oxidative Stress Response in Caenorhabditis elegans 
      Requires the GATA Transcription Factor ELT-3 and SKN-1/Nrf2.
  - statement: SKN-1 overexpression extends lifespan via ELT-3
    supporting_text: The Oxidative Stress Response in Caenorhabditis elegans 
      Requires the GATA Transcription Factor ELT-3 and SKN-1/Nrf2.
- id: PMID:34407394
  title: Tribbles pseudokinase NIPI-3 regulates intestinal immunity in 
    Caenorhabditis elegans by controlling SKN-1/Nrf activity.
  findings:
  - statement: NIPI-3 positively regulates SKN-1 activity
    supporting_text: Tribbles pseudokinase NIPI-3 regulates intestinal immunity 
      in Caenorhabditis elegans by controlling SKN-1/Nrf activity.
  - statement: SKN-1 nuclear translocation during pathogen infection
    supporting_text: Tribbles pseudokinase NIPI-3 regulates intestinal immunity 
      in Caenorhabditis elegans by controlling SKN-1/Nrf activity.
  - statement: Defense response to P. aeruginosa and E. faecalis
    supporting_text: Tribbles pseudokinase NIPI-3 regulates intestinal immunity 
      in Caenorhabditis elegans by controlling SKN-1/Nrf activity.
- id: file:worm/skn-1/skn-1-deep-research-falcon.md
  title: Deep research report on skn-1
  findings: []
- id: file:worm/skn-1/skn-1-hypotheses/translation-regulation-overannotation/openscientist.md
  title: 'OpenScientist hypothesis run: SKN-1 translation-regulation (GO:0006417) over-annotation'
  findings:
  - statement: Non-structural (domain/regulatory) analysis concluded that GO:0006417
      (regulation of translation, IEA from UniProt keyword KW-0810) is an over-annotation;
      SKN-1 lacks any RNA-binding or translation-factor domain and acts only as a
      transcription factor, with the keyword conflating activation BY translation
      inhibition with direct translation regulation.
    supporting_text: The curation recommendation is to remove GO:0006417 from P34707
      and to flag UniProtKB keyword KW-0810 for removal from this entry.
core_functions:
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: SKN-1 is a CNC/bZIP family transcription factor that binds DNA as
    a monomer through a unique mechanism. It activates transcription of Phase II
    detoxification genes, stress response genes, and developmental target genes.
- molecular_function:
    id: GO:0043565
    label: sequence-specific DNA binding
  description: SKN-1 binds DNA through the Skn domain which has a novel fold 
    combining a bZIP-like basic region with an N-terminal arm for minor groove 
    contacts.
  directly_involved_in:
  - id: GO:0006979
    label: response to oxidative stress
  - id: GO:1990748
    label: cellular detoxification
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: Maternal SKN-1 is essential for specification of the EMS 
    blastomere fate during early embryogenesis. SKN-1 activates MED-1/2 which in
    turn activate END-1/3 for endoderm specification.
  directly_involved_in:
  - id: GO:0048382
    label: mesendoderm development
  - id: GO:0001714
    label: endodermal cell fate specification
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: SKN-1 promotes longevity through activation of stress resistance 
    and metabolic adaptation programs. SKN-1 is required for lifespan extension 
    by reduced insulin/IGF-1 signaling, TOR inhibition, and dietary restriction.
  directly_involved_in:
  - id: GO:0008340
    label: determination of adult lifespan
proposed_new_terms: []
suggested_questions:
- question: What are the specific DNA binding sites and target gene repertoires 
    for each SKN-1 isoform?
- question: How does SKN-1 coordinate with other stress-responsive transcription
    factors like DAF-16 and HSF-1?
- question: What determines whether SKN-1 activates oxidative stress genes 
    versus innate immunity genes?
suggested_experiments:
- description: ChIP-seq analysis comparing SKN-1 binding sites under different 
    stress conditions
- description: Isoform-specific RNA-seq to distinguish SKN-1A, B, and C target 
    genes
- description: Genetic screens for additional SKN-1 regulators in the 
    WDR-23-independent pathway
tags:
- caeel-proteostasis
- caeel-mitophagy
- caeel-surveillance-immunity