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.
  molecular_function:
    id: GO:0003674
    label: molecular_function
  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