lin-65

---
id: Q95XN0
gene_symbol: lin-65
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: LIN-65 is a nuclear co-factor required for the mitochondrial unfolded
  protein response (UPR-mt) in C. elegans. It functions together with the histone
  H3K9 methyltransferase MET-2 to promote chromatin reorganization during mitochondrial
  stress. LIN-65 is required for the establishment of H3K9 di-methylation marks that
  lead to global chromatin silencing while allowing selective gene expression at stress-responsive
  loci. The protein contains multiple disordered regions, acidic domains, and a coiled-coil
  region, consistent with a scaffolding/regulatory role rather than direct catalytic
  function. LIN-65 translocates between cytosol and nucleus, with nuclear accumulation
  occurring during mitochondrial stress to mediate the epigenetic response that promotes
  longevity.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:27133166
    review:
      summary: LIN-65 was shown by direct assay (IDA) to localize to the nucleus.
        The publication PMID:27133166 demonstrates that LIN-65 functions as a "nuclear
        co-factor" that works with the histone methyltransferase MET-2 to mediate
        chromatin changes during mitochondrial stress. Nuclear localization is essential
        for its role in establishing H3K9me2 marks.
      action: ACCEPT
      reason: This annotation is well-supported by the evidence. The abstract of PMID:27133166
        explicitly describes LIN-65 as a "nuclear co-factor" and the GOA entry uses
        the qualifier "located_in" and "is_active_in" for the nucleus, both of which
        are appropriate given LIN-65's function in mediating chromatin changes through
        H3K9 di-methylation.
      supported_by:
        - reference_id: PMID:27133166
          supporting_text: Mitochondrial stress response activation requires the di-methylation
            of histone H3K9 through the activity of the histone methyltransferase
            met-2 and the nuclear co-factor lin-65.
  - term:
      id: GO:0034514
      label: mitochondrial unfolded protein response
    evidence_type: IDA
    original_reference_id: PMID:27133166
    review:
      summary: LIN-65 is directly involved in the mitochondrial unfolded protein response
        (UPR-mt). PMID:27133166 demonstrates that LIN-65, along with MET-2, is required
        for UPR-mt activation through chromatin reorganization. The protein mediates
        the epigenetic response to mitochondrial stress that results in transcriptional
        upregulation of protective genes.
      action: ACCEPT
      reason: This is a core function of LIN-65. The Tian et al. 2016 paper explicitly
        identifies LIN-65 as essential for UPR-mt activation. While LIN-65 acts at
        the chromatin level rather than directly sensing mitochondrial stress, its
        role in chromatin reorganization is an integral part of the UPR-mt signaling
        cascade.
      supported_by:
        - reference_id: PMID:27133166
          supporting_text: Mitochondrial stress response activation requires the di-methylation
            of histone H3K9 through the activity of the histone methyltransferase
            met-2 and the nuclear co-factor lin-65.
  - term:
      id: GO:0006338
      label: chromatin remodeling
    evidence_type: IMP
    original_reference_id: PMID:27133166
    review:
      summary: LIN-65 is required for chromatin reorganization during mitochondrial
        stress. PMID:27133166 shows that LIN-65, as a nuclear co-factor of MET-2,
        participates in establishing H3K9 di-methylation marks that lead to widespread
        chromatin silencing while allowing selective regions to remain open for stress-responsive
        transcription.
      action: ACCEPT
      reason: This annotation accurately reflects LIN-65's function. The term "chromatin
        remodeling" (GO:0006338) describes dynamic chromatin reorganization, which
        is precisely what LIN-65 mediates. The paper demonstrates that mitochondrial
        stress causes "widespread changes in chromatin structure" and that LIN-65
        is required for this process.
      supported_by:
        - reference_id: PMID:27133166
          supporting_text: We find that mitochondrial stress causes widespread changes
            in chromatin structure through histone H3K9 di-methylation marks traditionally
            associated with gene silencing.
  - term:
      id: GO:0003674
      label: molecular_function
    evidence_type: ND
    original_reference_id: GO_REF:0000015
    review:
      summary: This is a placeholder annotation indicating no specific molecular function
        has been experimentally determined for LIN-65. The protein is described as
        a "nuclear co-factor" but does not have characterized enzymatic activity.
      action: ACCEPT
      reason: This ND (No biological Data) annotation is appropriate. LIN-65 is described
        as a "nuclear co-factor" in the literature but lacks defined catalytic activity.
        The protein appears to function as a scaffolding or regulatory protein facilitating
        MET-2's histone methyltransferase activity, but no specific molecular function
        (e.g., protein binding, enzyme activity) has been experimentally characterized.
        The UniProt entry also lacks any functional domains beyond disordered regions
        and a coiled-coil.
      additional_reference_ids: [GO_REF:0000015]
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: PMID:27133166
    review:
      summary: LIN-65 was detected in the cytosol by direct assay. Given that LIN-65
        also localizes to the nucleus, this suggests the protein shuttles between
        compartments. Cytosolic localization may represent the protein's location
        under basal conditions or during specific phases of the stress response.
      action: ACCEPT
      reason: This annotation reflects observed localization data. LIN-65's presence
        in both cytosol and nucleus is consistent with a protein that translocates
        to the nucleus upon mitochondrial stress to mediate chromatin changes. Dual
        localization is commonly observed for signaling proteins involved in stress
        responses.
      supported_by:
        - reference_id: PMID:27133166
          supporting_text: Mitochondrial stress response activation requires the di-methylation
            of histone H3K9 through the activity of the histone methyltransferase
            met-2 and the nuclear co-factor lin-65. [The cytosolic localization may
            represent basal state distribution before nuclear translocation during
            stress]
  - term:
      id: GO:0034514
      label: mitochondrial unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:27133166
    review:
      summary: This is a second annotation to the same term (GO:0034514) but with
        IMP evidence rather than IDA. The mutant phenotype evidence demonstrates that
        loss of lin-65 function impairs the UPR-mt, confirming its essential role
        in this stress response pathway.
      action: ACCEPT
      reason: While this is a duplicate GO term, the different evidence code (IMP
        vs IDA) reflects distinct experimental approaches. IMP evidence from mutant
        analysis provides complementary support for LIN-65's role in UPR-mt. Both
        annotations can be retained as they represent different lines of evidence
        supporting the same biological role.
      supported_by:
        - reference_id: PMID:27133166
          supporting_text: Mitochondrial stress response activation requires the di-methylation
            of histone H3K9 through the activity of the histone methyltransferase
            met-2 and the nuclear co-factor lin-65.
  - term:
      id: GO:0031507
      label: heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:27133166
    review:
      summary: LIN-65 is required for heterochromatin formation during mitochondrial
        stress through its role in promoting H3K9 di-methylation, a hallmark of heterochromatin.
        This is a more specific annotation than the existing chromatin remodeling
        annotation.
      action: NEW
      reason: PMID:27133166 demonstrates that LIN-65 and MET-2 mediate H3K9 di-methylation,
        which is specifically associated with heterochromatin formation and gene silencing.
        The paper states that "globally the chromatin becomes silenced by these marks."
        This more specific term (GO:0031507) better captures LIN-65's role in establishing
        silenced chromatin than the general "chromatin remodeling" term.
      supported_by:
        - reference_id: PMID:27133166
          supporting_text: We find that mitochondrial stress causes widespread changes
            in chromatin structure through histone H3K9 di-methylation marks traditionally
            associated with gene silencing.
references:
  - id: GO_REF:0000015
    title: Use of the ND evidence code for Gene Ontology (GO) terms
    findings: []
  - id: PMID:27133166
    title: Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity
      and UPR(mt).
    findings:
      - statement: LIN-65 is a nuclear co-factor that works with the histone methyltransferase
          MET-2 to establish H3K9 di-methylation during mitochondrial stress
        supporting_text: Mitochondrial stress response activation requires the di-methylation
          of histone H3K9 through the activity of the histone methyltransferase met-2
          and the nuclear co-factor lin-65.
      - statement: Mitochondrial stress causes widespread chromatin changes through
          H3K9me2 marks, with LIN-65 being required for this response
        supporting_text: We find that mitochondrial stress causes widespread changes
          in chromatin structure through histone H3K9 di-methylation marks traditionally
          associated with gene silencing.
      - statement: The chromatin reorganization mediated by LIN-65 and MET-2 promotes
          UPR-mt activation and lifespan extension
        supporting_text: a metabolic stress response is established and propagated
          into adulthood of animals through specific epigenetic modifications that
          allow for selective gene expression and lifespan extension.
core_functions:
  - description: LIN-65 functions as a nuclear co-factor in the mitochondrial unfolded
      protein response, working with MET-2 to mediate chromatin reorganization through
      H3K9 di-methylation. While no specific molecular function has been characterized,
      LIN-65 appears to act as a scaffolding protein facilitating chromatin remodeling
      during stress responses.
    directly_involved_in:
      - id: GO:0034514
        label: mitochondrial unfolded protein response
      - id: GO:0006338
        label: chromatin remodeling
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0005829
        label: cytosol
proposed_new_terms: []
suggested_questions:
  - question: What is the precise molecular mechanism by which LIN-65 promotes MET-2's
      H3K9 methyltransferase activity? Does LIN-65 directly bind to MET-2?
  - question: What regulates LIN-65's nuclear translocation during mitochondrial stress?
      Are there specific post-translational modifications involved?
  - question: Does LIN-65 have any role in transgenerational inheritance of UPR-mt
      memory, and if so, how does this relate to its chromatin remodeling function?
suggested_experiments:
  - description: Co-immunoprecipitation studies to determine whether LIN-65 directly
      interacts with MET-2 and to identify other components of the chromatin remodeling
      complex
  - description: ChIP-seq analysis of LIN-65 binding sites to determine if it directly
      associates with chromatin regions undergoing H3K9 methylation during stress
  - description: Structure-function analysis of LIN-65's domains (coiled-coil, acidic
      regions) to determine which are required for its nuclear localization and co-factor
      function
tags: [caeel-upr-stress]