Dnaja3

id: Q99M87
gene_symbol: Dnaja3
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: >-
  Dnaja3 (also known as Tid1 or mTid-1) is a mitochondrial DnaJ/HSP40 family co-chaperone
  (subfamily A, member 3) that functions as a J-domain co-chaperone for mitochondrial HSP70
  (HSPA9/mortalin/GRP75). It is the mouse homolog of Drosophila tumor suppressor Tid56.
  Through its conserved J domain, Dnaja3 activates the ATPase activity of HSPA9 and delivers
  substrate proteins, including DNA polymerase gamma (Polg), which is critical for
  mitochondrial DNA replication and mitochondrial biogenesis. Dnaja3 knockout is embryonic
  lethal (PMID:14993262), and cardiac-specific deletion causes dilated cardiomyopathy with
  progressive respiratory chain deficiency and decreased mitochondrial DNA copy number
  (PMID:16327803). Dnaja3 also plays roles in T cell development (PMID:15879105), cellular
  senescence via NF-kappaB signaling (PMID:15572682), neuromuscular junction development
  via interaction with MuSK (PMID:19038220), and modulation of apoptosis in an
  isoform-dependent manner. Three alternatively spliced isoforms exist with opposing effects
  on apoptosis: isoform 1 (Tid-1L) is pro-apoptotic while isoform 2 (Tid-1S) is anti-apoptotic.
  The protein also interacts with Ras GTPase-activating protein (RASA1/GAP) (PMID:11116152).
alternative_products:
- name: 1 (Tid-1L, TID1L)
  id: Q99M87-1
- name: 2 (Tid-1S, TID1S)
  id: Q99M87-2
  sequence_note: VSP_007427, VSP_007428
- name: '3'
  id: Q99M87-3
  sequence_note: VSP_007440
existing_annotations:
# ============================
# IBA annotations (3)
# ============================
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for mitochondrion organization. Dnaja3 is a mitochondrial co-chaperone
      essential for mitochondrial biogenesis. Cardiac-specific deletion in mice leads to
      progressive respiratory chain deficiency and decreased mitochondrial DNA copy number
      (PMID:16327803). This is also supported by IMP evidence from the same publication.
    action: ACCEPT
    reason: >-
      Well-supported core function. Dnaja3 is critical for mitochondrial biogenesis through
      its chaperone activity on Polg (DNA polymerase gamma) and maintenance of mitochondrial
      DNA (PMID:16327803). IBA annotation is phylogenetically consistent and experimentally
      validated in mouse.
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Mice deficient in Dnaja3 developed dilated cardiomyopathy (DCM) and died before 10 weeks of age. Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3."
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for mitochondrial localization. Dnaja3 has a mitochondrial transit
      peptide and is well-established as a mitochondrial protein. Multiple experimental
      studies confirm mitochondrial localization (PMID:11116152, PMID:16327803, PMID:14993262,
      PMID:18614015).
    action: ACCEPT
    reason: >-
      Core localization. Dnaja3 contains a mitochondrial transit peptide and is confirmed
      in the mitochondrial matrix by multiple IDA, IMP, and HDA annotations from independent
      publications.
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "the mitochondrial chaperone Hsp40, also known as Dnaja3 or Tid1, is differentially expressed during cardiac development and pathological hypertrophy"
      - reference_id: PMID:11116152
        supporting_text: "GAP and Tid-1 were shown to colocalize at perinuclear mitochondrial membranes in response to epidermal growth factor stimulation"
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein kinase binding. Human DNAJA3 interacts with JAK2 (a
      tyrosine kinase), and mouse Dnaja3 isoform 2 interacts with MUSK (a receptor
      tyrosine kinase) at the neuromuscular junction (PMID:19038220). The IBA is
      phylogenetically derived and consistent with known interactions.
    action: ACCEPT
    reason: >-
      Supported by experimental evidence. Dnaja3 interacts with multiple protein kinases
      including MUSK (PMID:19038220) and JAK2 (UniProt by similarity), consistent with
      this IBA annotation.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "We used two-hybrid screens to identify a protein, tumorous imaginal discs (Tid1), that binds to the cytoplasmic domain of muscle-specific kinase (MuSK)"
# ============================
# IEA annotations (23)
# ============================
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted annotation for immune system process. Dnaja3 is required for T cell
      development in thymus (PMID:15879105), and is involved in NF-kappaB signaling
      (PMID:15572682). However, this is a very broad term.
    action: ACCEPT
    reason: >-
      While very broad, this IEA is not incorrect given the experimentally validated roles
      in T cell development (PMID:15879105) and immune signaling. More specific annotations
      exist (e.g. T cell differentiation in thymus, activation-induced cell death of T cells)
      which carry more information, but this broader IEA is acceptable as a general umbrella.
    supported_by:
      - reference_id: PMID:15879105
        supporting_text: "Mice with tid1 specifically deleted in T cells developed thymic atrophy, with dramatic reduction of double-positive and single-positive thymocytes"
- term:
    id: GO:0002682
    label: regulation of immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted annotation for regulation of immune system process. Dnaja3 regulates
      T cell development and NF-kappaB signaling (PMID:15879105, PMID:15572682).
    action: ACCEPT
    reason: >-
      Broad IEA consistent with experimentally validated roles in T cell development and
      NF-kappaB signaling regulation. Not incorrect, though more specific annotations
      already exist.
    supported_by:
      - reference_id: PMID:15879105
        supporting_text: "tid1 is critical in early thymocyte development, especially during transition from the DN3 to double-positive stages"
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted annotation for signaling receptor binding. Dnaja3 binds MuSK (a
      receptor tyrosine kinase) and IFN-gamma receptor 2 chain (by similarity from human).
    action: ACCEPT
    reason: >-
      Consistent with known interactions. Dnaja3 isoform 2 binds the cytoplasmic domain
      of MuSK (PMID:19038220), and human ortholog interacts with IFN-gammaR2 chain. This
      broad IEA is supported, though more specific terms exist (protein kinase binding,
      type II interferon receptor binding).
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "We used two-hybrid screens to identify a protein, tumorous imaginal discs (Tid1), that binds to the cytoplasmic domain of muscle-specific kinase (MuSK), a major component of the agrin receptor"
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro-derived annotation for ATP binding based on DnaJ domain (IPR012724). However,
      DnaJ/HSP40 proteins do not themselves bind or hydrolyze ATP. They stimulate the ATPase
      of their HSP70 partner. The DnaJ domain mediates J-domain interaction with HSP70, not
      direct ATP binding.
    action: REMOVE
    reason: >-
      DnaJ/HSP40 co-chaperones do not bind ATP themselves. The J domain activates the ATPase
      activity of HSP70 partner proteins (HSPA9/mortalin in this case), but Dnaja3 itself is
      not an ATPase or ATP-binding protein. This is a systematic over-annotation from the
      InterPro DnaJ domain mapping. The UniProt entry does not list ATP binding as a function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted nuclear localization. Dnaja3 has been observed in the nucleus by
      immunofluorescence (PMID:11116152, IDA). Also supported by ISO from human ortholog.
    action: ACCEPT
    reason: >-
      Consistent with experimental IDA evidence from PMID:11116152 showing nuclear
      localization. Dnaja3 is primarily mitochondrial but has been detected in nucleus
      and cytosol.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "GAP and Tid-1 were shown to colocalize at perinuclear mitochondrial membranes in response to epidermal growth factor stimulation"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Combined automated annotation for mitochondrial matrix localization. Dnaja3 has a
      mitochondrial transit peptide and the mature protein resides in the mitochondrial
      matrix. UniProt annotation states "Mitochondrion matrix" by similarity.
    action: ACCEPT
    reason: >-
      Consistent with the protein's known biology. Dnaja3 has a transit peptide for
      mitochondrial import and functions as a co-chaperone in the mitochondrial matrix
      where it interacts with HSPA9 and Polg (PMID:16327803).
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Combined automated annotation for cytosol localization. Dnaja3 precursor form is
      cytoplasmic before mitochondrial import, and has been detected in cytosol by IDA
      (PMID:11116152, PMID:19038220).
    action: ACCEPT
    reason: >-
      Consistent with experimental IDA evidence. The precursor form of Dnaja3 is
      cytoplasmic, and the protein has been detected in the cytosol in multiple studies.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "both cytoplasmic precursor and mitochondrial mature forms of mTid-1 associate with GAP in vivo"
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro-derived annotation for protein folding based on DnaJ domain and HSP40/DnaJ
      peptide-binding domain. Dnaja3 is a J-domain co-chaperone that assists HSP70 in
      protein folding but is not itself an independent foldase.
    action: ACCEPT
    reason: >-
      While Dnaja3 does not independently fold proteins, it participates in the protein
      folding process as a co-chaperone of HSP70. Its chaperone activity on Polg is
      described as essential for mitochondrial biogenesis (PMID:16327803). The term
      "protein folding" is broad enough to encompass co-chaperone participation in the
      folding process.
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga"
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      UniProt keyword-mapped annotation for apoptotic process. Dnaja3 modulates apoptosis
      in an isoform-dependent manner and is tagged with the Apoptosis keyword in UniProt.
      Experimental IMP evidence also exists (PMID:16327803).
    action: ACCEPT
    reason: >-
      Well-supported. Dnaja3 isoform 1 promotes apoptosis while isoform 2 suppresses it
      (PMID:11116152, PMID:14993262). Cardiac deletion leads to apoptosis (PMID:16327803).
      This is a pleiotropic function of the protein.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "two of which correspond to the recently identified hTid-1(L) and hTid-1(S) forms of the human TID1 gene that exhibit opposing effects on apoptosis"
      - reference_id: PMID:14993262
        supporting_text: "Tid1 removal in these cells led to massive cell death"
- term:
    id: GO:0006950
    label: response to stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted annotation for response to stress. Dnaja3 is a heat shock protein
      family member (DnaJ/HSP40) involved in protein quality control and stress response.
    action: ACCEPT
    reason: >-
      Broad but not incorrect. As a DnaJ/HSP40 co-chaperone, Dnaja3 participates in
      the heat shock response and stress-induced protein quality control.
- term:
    id: GO:0007528
    label: neuromuscular junction development
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted annotation for neuromuscular junction development. This is strongly
      supported by experimental evidence (PMID:19038220) demonstrating that Tid1 is
      essential for agrin signaling at the NMJ.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with experimental IMP evidence (PMID:19038220). Dnaja3 knockdown disrupts
      AChR clustering and neuromuscular transmission. However, NMJ development is a
      tissue-specific function, not the core molecular co-chaperone activity.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "Knockdown of Tid1 by short hairpin RNA (shRNA) in skeletal muscle fibers dispersed synaptic AChR clusters and impaired neuromuscular transmission"
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      UniProt keyword-mapped annotation for zinc ion binding. Dnaja3 contains a CR-type
      zinc finger domain (residues 223-301) with four CXXCXGXG motifs that coordinate
      two zinc ions. This is a structural feature of DnaJ subfamily A proteins.
    action: ACCEPT
    reason: >-
      Correct. The UniProt entry documents eight zinc-coordinating cysteine residues in
      the CR-type zinc finger domain, binding two Zn(2+) ions. This is a conserved
      structural feature of type I DnaJ proteins.
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro-derived annotation for response to heat based on DnaJ domain. As a member
      of the HSP40 family, Dnaja3 would be expected to participate in the heat shock response.
    action: ACCEPT
    reason: >-
      Reasonable inference from DnaJ domain membership. Heat shock proteins including HSP40
      family members participate in the cellular response to heat stress.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted protein kinase binding, duplicating the IBA annotation. Supported by
      interaction with MuSK (PMID:19038220) and JAK2 (by similarity).
    action: ACCEPT
    reason: >-
      Consistent with IBA and ISO annotations for the same term, and supported by
      experimental evidence of MuSK interaction (PMID:19038220).
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro-derived annotation for heat shock protein binding based on the cysteine-rich
      domain (IPR001305). Dnaja3 binds HSP70 (HSPA9/mortalin) through its J domain; this
      is the fundamental function of all DnaJ proteins.
    action: ACCEPT
    reason: >-
      Core function. The J domain of Dnaja3 mediates its interaction with HSP70 family
      member HSPA9 (PMID:14993262). More specific Hsp70 protein binding annotations
      also exist (GO:0030544).
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 is the mammalian counterpart of the Drosophila tumor suppressor Tid56 and is also a DnaJ protein containing a conserved J domain through which it interacts with the heat shock protein 70 (Hsp70) family of chaperone proteins"
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted annotation for regulation of cell population proliferation. Dnaja3
      affects cell proliferation: its deletion reduces thymocyte proliferation
      (PMID:15879105), and it regulates senescence (PMID:15572682). ISO annotation for
      negative regulation of cell population proliferation also exists.
    action: ACCEPT
    reason: >-
      Broad but supported. Experimental evidence shows Dnaja3 regulates proliferation in
      T cells (PMID:15879105) and fibroblasts (PMID:15572682).
    supported_by:
      - reference_id: PMID:15879105
        supporting_text: "the subpopulation of DN4 thymocytes was measurably smaller because of reduced proliferation and significant cell death"
- term:
    id: GO:0043069
    label: negative regulation of programmed cell death
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted annotation for negative regulation of programmed cell death. This is
      supported by experimental IMP evidence (PMID:14993262) showing that Tid1 knockout
      leads to massive cell death, indicating Tid1 normally suppresses programmed cell death.
    action: ACCEPT
    reason: >-
      Consistent with IMP evidence (PMID:14993262). Tid1 removal leads to cell death, and
      isoform 2 specifically suppresses apoptosis. This IEA is consistent with the broader
      experimental picture.
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 removal in these cells led to massive cell death. The death of Tid1-deficient cells could be rescued by ectopic expression of wild-type Tid1"
- term:
    id: GO:0045211
    label: postsynaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      UniProt subcellular location mapping for postsynaptic membrane. Dnaja3 is recruited
      to the postsynaptic cell membrane of the NMJ through interaction with MuSK
      (PMID:19038220). Also supported by IDA evidence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with experimental IDA evidence (PMID:19038220). UniProt explicitly notes
      postsynaptic cell membrane localization via MuSK interaction. This is a tissue-specific
      NMJ localization, not the primary subcellular location.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates"
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      UniProt keyword-mapped annotation for metal ion binding. Dnaja3 has a CR-type zinc
      finger domain that binds two zinc ions. This is a parent term of zinc ion binding,
      which is also annotated.
    action: ACCEPT
    reason: >-
      Correct but redundant with the more specific zinc ion binding annotation (GO:0008270).
      Acceptable as a broader IEA.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro-derived annotation for unfolded protein binding based on DnaJ domain
      (IPR001305, IPR008971, IPR012724). Per the UPB project decision rules, J-domain
      co-chaperones are substrate adaptors and HSP70 ATPase activators, not independent
      foldases or holdases. They deliver substrates to HSP70 but do not independently
      bind unfolded proteins in the manner implied by GO:0051082.
    action: MODIFY
    reason: >-
      Per UPB project decision rules for J-domain co-chaperones: Dnaja3 is a standard
      J-domain co-chaperone (DnaJ subfamily A) that activates HSP70 ATPase and delivers
      substrates. It is not an independent foldase or holdase. There is no evidence of
      independent holdase activity (unlike DNAJB6/DNAJB8). GO:0044183 (protein folding
      chaperone) is used as pragmatic interim since GO:0003767 (co-chaperone activity)
      is obsolete.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 is the mammalian counterpart of the Drosophila tumor suppressor Tid56 and is also a DnaJ protein containing a conserved J domain through which it interacts with the heat shock protein 70 (Hsp70) family of chaperone proteins"
      - reference_id: PMID:16327803
        supporting_text: "Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga"
# ============================
# ISO annotations (27)
# ============================
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation transferred from human DNAJA3 (Q96EY1). Human TID1 modulates
      IFN-gamma-mediated transcriptional activity and NF-kappaB signaling. Tid1 contributes
      to senescence by acting as a repressor of NF-kappaB signaling (PMID:15572682),
      which can include transcriptional repression.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible based on human ortholog data and the known role of Tid1 in repressing
      NF-kappaB-mediated transcription (PMID:15572682). However, this is not the core
      molecular function of Dnaja3 - it is a downstream consequence of its co-chaperone
      activity on transcriptional regulators.
    supported_by:
      - reference_id: PMID:15572682
        supporting_text: "Tid1 contributes to senescence by acting as a repressor of NF-kappaB signaling"
- term:
    id: GO:0005133
    label: type II interferon receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation transferred from human DNAJA3 (Q96EY1). UniProt notes that Dnaja3
      interacts with the IFN-gammaR2 chain (by similarity). This represents a specific
      protein-protein interaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by similarity-based evidence from the human ortholog. Dnaja3 interaction
      with IFN-gammaR2 chain is documented in UniProt. This is a specific binding
      interaction rather than a core co-chaperone function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation for nuclear localization transferred from human DNAJA3. Also supported
      by direct IDA evidence in mouse (PMID:11116152).
    action: ACCEPT
    reason: >-
      Consistent with experimental IDA evidence in mouse (PMID:11116152).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation for cytoplasm localization. The precursor form of Dnaja3 is
      cytoplasmic before mitochondrial import (PMID:11116152).
    action: ACCEPT
    reason: >-
      Consistent with known biology. The cytoplasmic precursor form is well documented
      (PMID:11116152). Dnaja3 has also been detected at the cytoplasmic side of plasma
      membrane (PMID:19038220).
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "both cytoplasmic precursor and mitochondrial mature forms of mTid-1 associate with GAP in vivo"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation for mitochondrial localization from human ortholog. Extensively
      supported by multiple experimental annotations in mouse.
    action: ACCEPT
    reason: >-
      Redundant with IBA and multiple experimental (IDA, IMP, HDA) annotations but not
      incorrect. Well-established core localization.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation for mitochondrial matrix from human ortholog. Consistent with the
      transit peptide and known function in mitochondrial matrix.
    action: ACCEPT
    reason: >-
      Supported by protein structure (transit peptide) and functional data showing
      activity in the mitochondrial matrix (PMID:16327803).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation for cytosol from human ortholog. Also supported by IDA in mouse
      (PMID:11116152, PMID:19038220).
    action: ACCEPT
    reason: >-
      Consistent with experimental IDA evidence in mouse.
- term:
    id: GO:0005884
    label: actin filament
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation for actin filament co-localization from human ortholog. Note the
      GOA qualifier is "colocalizes_with" not "located_in", so this represents
      co-localization rather than direct localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      The colocalizes_with qualifier makes this a weaker assertion. Co-localization with
      actin filaments may relate to the NMJ signaling role (PMID:19038220) where
      cytoskeletal organization is important for AChR clustering, but this is not a
      primary localization.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation for protein folding from human ortholog. Dnaja3 participates in
      protein folding as a co-chaperone of HSP70 in the mitochondrial matrix.
    action: ACCEPT
    reason: >-
      Consistent with core function. Dnaja3 assists HSPA9 in folding mitochondrial
      client proteins including Polg (PMID:16327803). Protein folding is broad enough
      to encompass co-chaperone participation.
- term:
    id: GO:0007528
    label: neuromuscular junction development
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog for NMJ development. Also supported by direct
      IMP evidence in mouse (PMID:19038220).
    action: KEEP_AS_NON_CORE
    reason: >-
      Well-supported by direct experimental evidence in mouse (PMID:19038220), but this
      is a tissue-specific developmental function, not the core molecular function of
      Dnaja3. The primary role is as a mitochondrial co-chaperone.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "Tid1 is an essential component of the agrin signaling pathway, crucial for synaptic development"
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Dnaja3/Tid1 suppresses spontaneous
      immortalization and ectopic expression suppresses cell proliferation
      (PMID:15572682).
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by evidence from PMID:15572682, but this is a downstream consequence of
      Dnaja3's effects on NF-kappaB signaling and apoptosis regulation, not a core
      molecular function.
    supported_by:
      - reference_id: PMID:15572682
        supporting_text: "spontaneous immortalization of rat embryo fibroblasts is suppressed upon ectopic expression of Tid1"
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog for protein kinase binding. Consistent with IBA
      and direct mouse evidence for MuSK interaction (PMID:19038220).
    action: ACCEPT
    reason: >-
      Consistent with multiple lines of evidence including IBA and experimental data.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: >-
      ISO annotation transferred from rat ortholog via automated mouse-rat ortholog
      transfer. Core function of all DnaJ proteins is to bind HSP70 through their J
      domain. Dnaja3 binds HSPA9/mortalin (PMID:14993262).
    action: ACCEPT
    reason: >-
      Core function. The J domain of Dnaja3 mediates its essential interaction with HSP70
      (HSPA9). This interaction is required for cell survival (PMID:14993262).
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "The death of Tid1-deficient cells could be rescued by ectopic expression of wild-type Tid1 but not by expression of the Tid1 protein that had a mutated J domain and was thus incapable of binding to Hsp70"
- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog for positive regulation of protein
      ubiquitination. Some DnaJ co-chaperones can target substrates for ubiquitin-mediated
      degradation through the HSP70 chaperone system.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible for a co-chaperone that can target misfolded substrates for degradation,
      but this is a downstream consequence of co-chaperone function rather than a direct
      enzymatic activity. Not the core function.
- term:
    id: GO:0034341
    label: response to type II interferon
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. UniProt notes Dnaja3 can modulate IFN-gamma-mediated
      transcriptional activity (by similarity) and interacts with IFN-gammaR2 chain.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by similarity data from the human ortholog. IFN-gamma signaling modulation
      is a pleiotropic function of Dnaja3, not its core molecular activity.
- term:
    id: GO:0042645
    label: mitochondrial nucleoid
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog for mitochondrial nucleoid localization. Consistent
      with Dnaja3's role in mitochondrial DNA replication through its chaperone activity
      on Polg (PMID:16327803). Polg is part of the mitochondrial nucleoid.
    action: ACCEPT
    reason: >-
      Consistent with Dnaja3's function as a co-chaperone for Polg, the catalytic subunit
      of the mitochondrial DNA polymerase, which operates at the mitochondrial nucleoid
      (PMID:16327803).
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein"
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Dnaja3 isoform 1 (Tid-1L) increases apoptosis
      triggered by TNF and DNA-damaging agents (UniProt by similarity, PMID:11116152).
    action: KEEP_AS_NON_CORE
    reason: >-
      Isoform-specific function. Isoform 1 (Tid-1L) is pro-apoptotic while isoform 2
      (Tid-1S) is anti-apoptotic (PMID:11116152). This is a pleiotropic, isoform-dependent
      function rather than the core molecular activity.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "two of which correspond to the recently identified hTid-1(L) and hTid-1(S) forms of the human TID1 gene that exhibit opposing effects on apoptosis"
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Dnaja3 isoform 2 (Tid-1S) suppresses apoptosis
      (UniProt by similarity). Also, global Tid1 loss causes massive cell death
      (PMID:14993262), indicating the protein normally suppresses apoptosis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Isoform-dependent function. Isoform 2 is anti-apoptotic while isoform 1 is
      pro-apoptotic. The net effect of Tid1 loss is cell death (PMID:14993262), consistent
      with an overall pro-survival function. Non-core pleiotropic function.
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 removal in these cells led to massive cell death"
- term:
    id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Tid1 acts as a repressor of NF-kappaB signaling
      (PMID:15572682). Modulation of endogenous Tid1 activity alleviates suppression of
      TNF-alpha-induced NF-kappaB activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by experimental evidence in mouse (PMID:15572682). NF-kappaB signaling
      regulation is a downstream effect of Dnaja3 function, not the core molecular activity.
    supported_by:
      - reference_id: PMID:15572682
        supporting_text: "Modulation of endogenous Tid1 activity by GSE-Tid1 or Tid1-specific RNA interference alleviates the suppression of tumor necrosis factor alpha-induced NF-kappaB activity by Tid1"
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog for protein-containing complex binding. This is
      a very generic binding term. Dnaja3 does interact with multi-protein complexes
      (e.g., IkappaB kinase complex, HSP70 machinery).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Too generic. More specific binding terms are already annotated (Hsp70 protein binding,
      protein kinase binding, NF-kappaB binding, IkappaB kinase complex binding). This
      broad term does not add informative content.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Dnaja3's chaperone activity stabilizes client
      proteins such as Polg (PMID:16327803). Loss of Dnaja3 leads to decreased Polg
      stability and mitochondrial dysfunction.
    action: ACCEPT
    reason: >-
      Consistent with the co-chaperone function of Dnaja3. By assisting HSP70 in protein
      folding, Dnaja3 contributes to the stabilization of mitochondrial client proteins
      including Polg (PMID:16327803).
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein"
- term:
    id: GO:0051059
    label: NF-kappaB binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Tid1 represses NF-kappaB signaling
      (PMID:15572682), and NF-kappaB binding implies direct interaction with NF-kappaB
      transcription factors.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by the known role of Tid1 in NF-kappaB signaling regulation
      (PMID:15572682). However, this binding interaction is likely mediated through the
      co-chaperone machinery rather than direct transcription factor binding activity. It
      represents a non-core pleiotropic function.
    supported_by:
      - reference_id: PMID:15572682
        supporting_text: "NF-kappaB sequence-specific binding is strongly downregulated upon senescence in rat embryo fibroblasts"
- term:
    id: GO:0060336
    label: negative regulation of type II interferon-mediated signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. UniProt notes Dnaja3 can modulate
      IFN-gamma-mediated transcriptional activity (by similarity).
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible based on human ortholog data and IFN-gamma receptor binding. This is a
      downstream signaling role, not the core molecular function. Non-core annotation.
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. This suggests direct binding to RNA Pol II
      transcription factors, which may relate to the NF-kappaB and IFN-gamma signaling
      roles of Dnaja3.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible in the context of NF-kappaB binding (GO:0051059) and transcriptional
      regulation activities. However, these binding interactions likely represent
      co-chaperone-mediated effects rather than direct transcription factor binding
      activity. Non-core function.
- term:
    id: GO:0106137
    label: IkappaB kinase complex binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Consistent with Dnaja3's role in NF-kappaB
      signaling regulation (PMID:15572682). The IkappaB kinase complex is upstream of
      NF-kappaB activation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the NF-kappaB signaling regulation role. This specific binding
      interaction is a non-core function of the co-chaperone.
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      ISO annotation from human ortholog. Parent term of GO:0061629. Likely relates to
      NF-kappaB and IFN-gamma signaling interactions.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broader version of the RNA Pol II-specific TF binding annotation. Non-core
      pleiotropic function related to signaling roles.
# ============================
# IEA (Ensembl Compara) annotations (6)
# ============================
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara-transferred annotation from human DNAJA3. Duplicates the ISO
      annotation with the same GO term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with ISO annotation. Non-core pleiotropic function related to NF-kappaB
      signaling regulation (PMID:15572682).
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Combined automated annotation for mitochondrial localization. Redundant with IBA,
      ISO, and multiple experimental annotations.
    action: ACCEPT
    reason: >-
      Core localization, consistent with all other evidence.
- term:
    id: GO:0005884
    label: actin filament
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara-transferred annotation for actin filament co-localization.
      Duplicates the ISO annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with ISO annotation. Co-localization qualifier; non-core.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara-transferred annotation. Duplicates ISO annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with ISO and experimental data. Non-core pleiotropic function.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara-transferred Hsp70 protein binding. Core function of DnaJ proteins.
    action: ACCEPT
    reason: >-
      Core function consistent with ISO and fundamental DnaJ biology (PMID:14993262).
- term:
    id: GO:0042645
    label: mitochondrial nucleoid
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara-transferred mitochondrial nucleoid localization. Consistent with
      ISO annotation and Polg chaperone function.
    action: ACCEPT
    reason: >-
      Consistent with ISO annotation and Dnaja3's role in mitochondrial DNA replication
      through Polg chaperoning (PMID:16327803).
# ============================
# Experimental annotations (IDA, IMP, IPI, HDA) (22)
# ============================
- term:
    id: GO:0009898
    label: cytoplasmic side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:19038220
  review:
    summary: >-
      IDA annotation for cytoplasmic side of plasma membrane localization from
      PMID:19038220. Tid1 is recruited to the postsynaptic cell membrane of the NMJ
      through interaction with MuSK.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid experimental observation specific to the NMJ signaling context. Tid1 is
      recruited to the plasma membrane through MuSK interaction (PMID:19038220). This
      is a context-specific localization, not the primary location of the protein.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates"
- term:
    id: GO:0090398
    label: cellular senescence
  evidence_type: IDA
  original_reference_id: PMID:15572682
  review:
    summary: >-
      IDA annotation for cellular senescence from PMID:15572682. Tid1 expression is
      upregulated upon cellular senescence, and ectopic expression suppresses spontaneous
      immortalization. Tid1 contributes to senescence through NF-kappaB signaling
      repression.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid experimental observation. Dnaja3 is upregulated in senescent cells and
      promotes senescence (PMID:15572682). This is a pleiotropic function downstream
      of its effects on NF-kappaB signaling, not the core molecular function.
    supported_by:
      - reference_id: PMID:15572682
        supporting_text: "Expression of Tid1 is upregulated upon cellular senescence in rat and mouse embryo fibroblasts and premature senescence of REF52 cells triggered by activated ras"
- term:
    id: GO:0043069
    label: negative regulation of programmed cell death
  evidence_type: IMP
  original_reference_id: PMID:14993262
  review:
    summary: >-
      IMP annotation for negative regulation of programmed cell death from PMID:14993262.
      Tid1 knockout leads to massive cell death in embryonic fibroblasts, demonstrating
      that Tid1 normally suppresses programmed cell death. Cell death could be rescued
      by wild-type Tid1 but not J-domain mutant.
    action: ACCEPT
    reason: >-
      Strong experimental evidence. Tid1 removal causes massive cell death, which is
      rescued by wild-type Tid1 but not by J-domain mutant (PMID:14993262). This
      demonstrates Tid1 functions as a pro-survival factor through its HSP70
      co-chaperone activity.
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 removal in these cells led to massive cell death. The death of Tid1-deficient cells could be rescued by ectopic expression of wild-type Tid1 but not by expression of the Tid1 protein that had a mutated J domain and was thus incapable of binding to Hsp70"
- term:
    id: GO:0007264
    label: small GTPase-mediated signal transduction
  evidence_type: IDA
  original_reference_id: PMID:11116152
  review:
    summary: >-
      IDA annotation for small GTPase-mediated signal transduction from PMID:11116152.
      Dnaja3 binds to p120 RasGAP (RASA1) and may influence Ras signaling. At the NMJ,
      Tid1 is required for agrin-induced activation of Rac and Rho GTPases (PMID:19038220).
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by experimental evidence showing GAP binding (PMID:11116152) and Rac/Rho
      GTPase activation at the NMJ (PMID:19038220). However, this is a downstream
      consequence of Dnaja3 interactions rather than its core molecular function as a
      co-chaperone. The role may be in modulating GAP conformation/activity through
      co-chaperone function.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "Tid chaperone proteins may play a role in governing the conformation, activity, and/or subcellular distribution of GAP, thereby influencing its biochemical and biological activity within cells"
      - reference_id: PMID:19038220
        supporting_text: "Tid1 knockdown inhibited AChR clustering, as well as agrin-induced activation of the Rac and Rho small GTPases"
- term:
    id: GO:0030695
    label: GTPase regulator activity
  evidence_type: IDA
  original_reference_id: PMID:11116152
  review:
    summary: >-
      IDA annotation for GTPase regulator activity from PMID:11116152. Dnaja3 binds
      RasGAP, but the evidence suggests Dnaja3 may influence GAP activity rather than
      directly regulating GTPase activity. The paper describes Dnaja3 as a GAP-binding
      protein, not as a direct GTPase regulator.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The paper (PMID:11116152) describes Dnaja3 as a novel GAP-binding protein that may
      influence GAP conformation and activity through its chaperone function. It does not
      demonstrate direct GTPase regulator activity by Dnaja3 itself. The interaction with
      GAP could influence Ras signaling indirectly through co-chaperone-mediated effects
      on GAP, but annotating Dnaja3 as having GTPase regulator activity overstates the
      evidence.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "These findings raise the possibility that Tid chaperone proteins may play a role in governing the conformation, activity, and/or subcellular distribution of GAP, thereby influencing its biochemical and biological activity within cells"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:19038220
  review:
    summary: >-
      IDA annotation for cytosol localization from PMID:19038220. Detected in cytosol
      during NMJ studies.
    action: ACCEPT
    reason: >-
      Valid experimental observation. Consistent with other IDA evidence for cytosol
      localization (PMID:11116152).
- term:
    id: GO:0007528
    label: neuromuscular junction development
  evidence_type: IMP
  original_reference_id: PMID:19038220
  review:
    summary: >-
      IMP annotation for NMJ development from PMID:19038220. Tid1 knockdown in skeletal
      muscle fibers disperses synaptic AChR clusters and impairs neuromuscular
      transmission. Tid1 is essential for agrin signaling at the NMJ.
    action: KEEP_AS_NON_CORE
    reason: >-
      Strong experimental evidence for a specific developmental role. However, NMJ
      development is a tissue-specific pleiotropic function of Dnaja3, not its core
      molecular co-chaperone function.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "Knockdown of Tid1 by short hairpin RNA (shRNA) in skeletal muscle fibers dispersed synaptic AChR clusters and impaired neuromuscular transmission"
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: IDA
  original_reference_id: PMID:19038220
  review:
    summary: >-
      IDA annotation for NMJ localization from PMID:19038220. Tid1 colocalizes with AChRs
      at developing, adult, and denervated motor endplates.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid experimental observation of tissue-specific localization. Context-dependent
      localization related to NMJ signaling function, not primary subcellular location.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates"
- term:
    id: GO:0045211
    label: postsynaptic membrane
  evidence_type: IDA
  original_reference_id: PMID:19038220
  review:
    summary: >-
      IDA annotation for postsynaptic membrane localization from PMID:19038220. Tid1 is
      recruited to the postsynaptic cell membrane of the NMJ through interaction with MuSK.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid experimental observation. Tissue-specific localization at the NMJ, mediated
      by MuSK interaction (PMID:19038220). Non-core localization.
    supported_by:
      - reference_id: PMID:19038220
        supporting_text: "Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:18614015
  review:
    summary: >-
      HDA annotation for mitochondrial localization from the MitoCarta proteomic study
      (PMID:18614015). Dnaja3 was identified in the mitochondrial protein compendium
      through mass spectrometry analysis across 14 mouse tissues.
    action: ACCEPT
    reason: >-
      Strong proteomic evidence from the comprehensive MitoCarta study. Consistent with
      all other evidence for mitochondrial localization.
    supported_by:
      - reference_id: PMID:18614015
        supporting_text: "we performed mass spectrometry, GFP tagging, and machine learning to create a mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14993262
  review:
    summary: >-
      IPI annotation for protein binding with PR:P38647 (mouse HSPA9/mortalin, the
      mitochondrial HSP70). Tid1 interacts with HSPA9 through its J domain (PMID:14993262).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interaction with HSPA9 is real and critical, but "protein binding" is
      uninformative. The more specific term GO:0030544 (Hsp70 protein binding) is already
      annotated and better captures this interaction.
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 is the mammalian counterpart of the Drosophila tumor suppressor Tid56 and is also a DnaJ protein containing a conserved J domain through which it interacts with the heat shock protein 70 (Hsp70) family of chaperone proteins"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16327803
  review:
    summary: >-
      IPI annotation for protein binding with PR:P54099 (mouse Polg, DNA polymerase
      gamma-1). Polg was identified as a Dnaja3-interacting client protein in the
      cardiomyopathy study (PMID:16327803).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interaction with Polg is real and functionally significant, but "protein
      binding" is uninformative. The interaction represents co-chaperone-mediated client
      protein binding, which is not well captured by current GO terms. The protein
      stabilization annotation (GO:0050821) better reflects this functional relationship.
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:14993262
  review:
    summary: >-
      IMP annotation for mitochondrial localization from PMID:14993262, based on knockout
      studies where Tid1 deletion leads to mitochondrial dysfunction.
    action: ACCEPT
    reason: >-
      Consistent with all other evidence for mitochondrial localization.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:16327803
  review:
    summary: >-
      IDA annotation for mitochondrial localization from PMID:16327803. Dnaja3 is
      described as "the mitochondrial chaperone Hsp40."
    action: ACCEPT
    reason: >-
      Direct experimental evidence for core localization.
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "the mitochondrial chaperone Hsp40, also known as Dnaja3 or Tid1"
- term:
    id: GO:0006264
    label: mitochondrial DNA replication
  evidence_type: IMP
  original_reference_id: PMID:16327803
  review:
    summary: >-
      IMP annotation for mitochondrial DNA replication from PMID:16327803. Cardiac-specific
      Dnaja3 deletion leads to decreased mitochondrial DNA copy number, and Polg (the
      mitochondrial DNA polymerase) is a client protein of Dnaja3.
    action: ACCEPT
    reason: >-
      Strong experimental evidence. Dnaja3 deletion causes decreased mtDNA copy number,
      and Polg is identified as a Dnaja3 client protein (PMID:16327803). This represents
      a key biological process downstream of the co-chaperone function.
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3. Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein."
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:16327803
  review:
    summary: >-
      IMP annotation for apoptotic process from PMID:16327803. Cardiac-specific Dnaja3
      deletion leads to cardiomyocyte death and dilated cardiomyopathy.
    action: ACCEPT
    reason: >-
      Experimental evidence showing that Dnaja3 loss leads to cell death in
      cardiomyocytes (PMID:16327803), consistent with the broader role in cell survival.
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Mice deficient in Dnaja3 developed dilated cardiomyopathy (DCM) and died before 10 weeks of age"
- term:
    id: GO:0006924
    label: activation-induced cell death of T cells
  evidence_type: IMP
  original_reference_id: PMID:15879105
  review:
    summary: >-
      IMP annotation for activation-induced cell death of T cells from PMID:15879105.
      T cell-specific Tid1 deletion causes significant cell death in DN4 thymocytes
      during development.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid experimental observation from T cell-specific knockout (PMID:15879105).
      This is a tissue-specific manifestation of Dnaja3's pro-survival function rather
      than its core molecular activity. The cell death is due to loss of Bcl-2 expression.
    supported_by:
      - reference_id: PMID:15879105
        supporting_text: "the subpopulation of DN4 thymocytes was measurably smaller because of reduced proliferation and significant cell death"
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IMP
  original_reference_id: PMID:16327803
  review:
    summary: >-
      IMP annotation for mitochondrion organization from PMID:16327803. Cardiac-specific
      Dnaja3 deletion leads to progressive respiratory chain deficiency, consistent with
      a role in mitochondrial biogenesis and organization.
    action: ACCEPT
    reason: >-
      Core function. Strong experimental evidence that Dnaja3 is essential for
      mitochondrial biogenesis and organization (PMID:16327803).
    supported_by:
      - reference_id: PMID:16327803
        supporting_text: "Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3"
- term:
    id: GO:0033077
    label: T cell differentiation in thymus
  evidence_type: IMP
  original_reference_id: PMID:15879105
  review:
    summary: >-
      IMP annotation for T cell differentiation in thymus from PMID:15879105. T cell-specific
      Tid1 deletion blocks the DN3 to DP transition in thymic T cell development.
    action: KEEP_AS_NON_CORE
    reason: >-
      Strong experimental evidence from T cell-specific knockout (PMID:15879105). This is
      a tissue-specific developmental function, not the core molecular co-chaperone activity.
    supported_by:
      - reference_id: PMID:15879105
        supporting_text: "tid1 is critical in early thymocyte development, especially during transition from the DN3 to double-positive stages, possibly through its regulation of bcl-2 expression"
- term:
    id: GO:0042102
    label: positive regulation of T cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:15879105
  review:
    summary: >-
      IMP annotation for positive regulation of T cell proliferation from PMID:15879105.
      Tid1 deletion reduces thymocyte proliferation, indicating Tid1 normally promotes
      T cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid experimental observation (PMID:15879105). This is a tissue-specific
      pleiotropic function rather than the core molecular activity.
    supported_by:
      - reference_id: PMID:15879105
        supporting_text: "the subpopulation of DN4 thymocytes was measurably smaller because of reduced proliferation and significant cell death"
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IPI
  original_reference_id: PMID:11116152
  review:
    summary: >-
      IPI annotation for unfolded protein binding from PMID:11116152, with evidence of
      interaction with Q61698 (mouse HSP68/HSP70). Per the UPB project, J-domain
      co-chaperones are substrate adaptors and HSP70 ATPase activators, not independent
      holders or folders of unfolded proteins. The with/from field indicates interaction
      with HSP70, which is the Hsp70 protein binding interaction, not direct unfolded
      protein binding.
    action: MODIFY
    reason: >-
      Per UPB project decision rules for J-domain co-chaperones: Dnaja3 is a standard
      J-domain co-chaperone (DnaJ subfamily A, type I) that activates HSP70 ATPase and
      delivers substrates. It is not an independent foldase or holdase. The IPI evidence
      with Q61698 (HSP68/HSP70) actually demonstrates HSP70 binding, not unfolded protein
      binding per se. GO:0044183 (protein folding chaperone) is used as pragmatic interim
      for co-chaperone function since GO:0003767 is obsolete.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 is the mammalian counterpart of the Drosophila tumor suppressor Tid56 and is also a DnaJ protein containing a conserved J domain through which it interacts with the heat shock protein 70 (Hsp70) family of chaperone proteins"
      - reference_id: PMID:16327803
        supporting_text: "Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga"
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11116152
  review:
    summary: >-
      IDA annotation for nuclear localization from PMID:11116152. Immunofluorescence
      showed Tid1 localization, including at perinuclear regions and in the nucleus.
    action: ACCEPT
    reason: >-
      Direct experimental evidence. While Dnaja3 is primarily mitochondrial, nuclear
      localization has been experimentally observed.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:11116152
  review:
    summary: >-
      IDA annotation for mitochondrial localization from PMID:11116152. Immunofluorescence
      showed Tid1 at perinuclear mitochondrial membranes.
    action: ACCEPT
    reason: >-
      Core localization with direct experimental evidence.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "GAP and Tid-1 were shown to colocalize at perinuclear mitochondrial membranes in response to epidermal growth factor stimulation"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:11116152
  review:
    summary: >-
      IDA annotation for cytosol localization from PMID:11116152. The cytoplasmic
      precursor form of Dnaja3 was detected.
    action: ACCEPT
    reason: >-
      Direct experimental evidence. The precursor form is cytoplasmic before
      mitochondrial import.
    supported_by:
      - reference_id: PMID:11116152
        supporting_text: "both cytoplasmic precursor and mitochondrial mature forms of mTid-1 associate with GAP in vivo"
# ============================
# Missing GOA annotation - third protein binding IPI
# ============================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16327803
  review:
    summary: >-
      IPI annotation for protein binding with UniProtKB:P38646 (human HSPA9/mortalin/GRP75,
      the mitochondrial HSP70). This annotation was present in the GOA but missing from
      the initial review YAML. Dnaja3 interacts with HSPA9 through its J domain.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interaction with HSPA9 is real and functionally critical, but "protein binding"
      is uninformative. The more specific term GO:0030544 (Hsp70 protein binding) is
      already annotated and better captures this interaction. Also note P38646 is the
      human HSPA9 accession, while P38647 is the mouse ortholog already captured in
      the first protein binding IPI annotation.
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "Tid1 is the mammalian counterpart of the Drosophila tumor suppressor Tid56 and is also a DnaJ protein containing a conserved J domain through which it interacts with the heat shock protein 70 (Hsp70) family of chaperone proteins"
# ============================
# NEW suggested annotations
# ============================
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IPI
  original_reference_id: PMID:16327803
  review:
    summary: >-
      Proposed new annotation for protein folding chaperone activity (interim for
      co-chaperone function). Dnaja3 functions as a J-domain co-chaperone for
      mitochondrial HSP70 (HSPA9), activating its ATPase activity and delivering
      substrate proteins including Polg. This is the replacement for the two
      GO:0051082 unfolded protein binding annotations that were marked for MODIFY.
    action: NEW
    reason: >-
      Per UPB project decision rules, J-domain co-chaperones should be annotated to
      GO:0044183 as pragmatic interim since GO:0003767 (co-chaperone activity) is
      obsolete. Dnaja3 activates HSP70 ATPase via its J domain and delivers substrates
      (Polg, etc.) for folding. This captures the essential co-chaperone function better
      than GO:0051082 (unfolded protein binding).
    proposed_replacement_terms: []
    supported_by:
      - reference_id: PMID:14993262
        supporting_text: "The death of Tid1-deficient cells could be rescued by ectopic expression of wild-type Tid1 but not by expression of the Tid1 protein that had a mutated J domain and was thus incapable of binding to Hsp70"
      - reference_id: PMID:16327803
        supporting_text: "Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga"
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, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000096
  title: Automated transfer of experimentally-verified manual GO annotation data to
    mouse-rat orthologs
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000119
  title: Automated transfer of experimentally-verified manual GO annotation data to
    mouse-human orthologs
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11116152
  title: A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines
    a novel Ras GTPase-activating protein (RasGAP)-binding protein.
  findings: []
- id: PMID:14993262
  title: Tid1, a cochaperone of the heat shock 70 protein and the mammalian counterpart
    of the Drosophila tumor suppressor l(2)tid, is critical for early embryonic development
    and cell survival.
  findings: []
- id: PMID:15572682
  title: 'Functional genetic screen for genes involved in senescence: role of Tid1,
    a homologue of the Drosophila tumor suppressor l(2)tid, in senescence and cell
    survival.'
  findings: []
- id: PMID:15879105
  title: Tid1 is required for T cell transition from double-negative 3 to double-positive
    stages.
  findings: []
- id: PMID:16327803
  title: A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy.
  findings: []
- id: PMID:18614015
  title: A mitochondrial protein compendium elucidates complex I disease biology.
  findings: []
- id: PMID:19038220
  title: A mammalian homolog of Drosophila tumorous imaginal discs, Tid1, mediates
    agrin signaling at the neuromuscular junction.
  findings: []