Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007005 mitochondrion organization	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:16327803 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. file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	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). 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. Supporting Evidence: PMID:16327803 the mitochondrial chaperone Hsp40, also known as Dnaja3 or Tid1, is differentially expressed during cardiac development and pathological hypertrophy PMID:11116152 GAP and Tid-1 were shown to colocalize at perinuclear mitochondrial membranes in response to epidermal growth factor stimulation file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0019901 protein kinase binding	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:19038220 We used two-hybrid screens to identify a protein, tumorous imaginal discs (Tid1), that binds to the cytoplasmic domain of muscle-specific kinase (MuSK)
GO:0002376 immune system process	IEA GO_REF:0000117	KEEP AS NON CORE	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. Reason: This broad immune-system umbrella is compatible with tissue-specific T/B-cell phenotypes, but it is downstream of the mitochondrial Hsp70 co-chaperone role and should not be retained as a core function. Supporting Evidence: PMID:15879105 Mice with tid1 specifically deleted in T cells developed thymic atrophy, with dramatic reduction of double-positive and single-positive thymocytes file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md DNAJA3 is required for B cell development, mitochondrial function, and humoral immune output
GO:0002682 regulation of immune system process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA-predicted annotation for regulation of immune system process. Dnaja3 regulates T cell development and NF-kappaB signaling (PMID:15879105, PMID:15572682). Reason: Broad IEA consistent with tissue-specific immune phenotypes and NF-kappaB signaling regulation, but this is downstream/pleiotropic biology rather than the core mitochondrial co-chaperone function. Supporting Evidence: PMID:15879105 tid1 is critical in early thymocyte development, especially during transition from the DN3 to double-positive stages file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md DNAJA3 is required for B cell development, mitochondrial function, and humoral immune output
GO:0005102 signaling receptor binding	IEA GO_REF:0000117	ACCEPT	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). 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). Supporting Evidence: PMID:19038220 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
GO:0005524 ATP binding	IEA GO_REF:0000002	REMOVE	Summary: ATP binding is not supported for Dnaja3 itself. DnaJ/Hsp40 proteins stimulate ATP cycling on Hsp70 partners rather than acting as ATP-binding enzymes. Reason: This is a domain-transfer overannotation from DnaJ/Hsp40 family context; the ATPase belongs to the Hsp70 partner, not Dnaja3. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Dnaja3 should not be annotated as ATP binding solely because it has a DnaJ domain
GO:0005634 nucleus	IEA GO_REF:0000117	MODIFY	Summary: ARBA-predicted nuclear localization is not supported by the cached local evidence. PMID:11116152 supports cytoplasmic precursor/mitochondrial mature forms and perinuclear mitochondrial membranes, not nuclear localization. Reason: Replace the unsupported nuclear localization with the mitochondrial localization supported by the available evidence. Proposed replacements: mitochondrion Supporting Evidence: PMID:11116152 GAP and Tid-1 were shown to colocalize at perinuclear mitochondrial membranes in response to epidermal growth factor stimulation
GO:0005759 mitochondrial matrix	IEA GO_REF:0000120	ACCEPT	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. 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). Supporting Evidence: PMID:16327803 Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005829 cytosol	IEA GO_REF:0000120	ACCEPT	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). 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. Supporting Evidence: PMID:11116152 both cytoplasmic precursor and mitochondrial mature forms of mTid-1 associate with GAP in vivo
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	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. 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. Supporting Evidence: PMID:16327803 Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0006915 apoptotic process	IEA GO_REF:0000043	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:11116152 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 PMID:14993262 Tid1 removal in these cells led to massive cell death
GO:0006950 response to stress	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	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. Reason: This broad stress-response IEA is inferred from DnaJ/HSP40 family context and lacks Dnaja3-specific local support as a core function.
GO:0007528 neuromuscular junction development	IEA GO_REF:0000117	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:19038220 Knockdown of Tid1 by short hairpin RNA (shRNA) in skeletal muscle fibers dispersed synaptic AChR clusters and impaired neuromuscular transmission
GO:0008270 zinc ion binding	IEA GO_REF:0000043	ACCEPT	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. 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.
GO:0009408 response to heat	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	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. Reason: This heat-response annotation is based on DnaJ domain membership, but local evidence supports mitochondrial Hsp70 co-chaperone activity rather than a Dnaja3-specific heat-response role.
GO:0019901 protein kinase binding	IEA GO_REF:0000117	ACCEPT	Summary: ARBA-predicted protein kinase binding, duplicating the IBA annotation. Supported by interaction with MuSK (PMID:19038220) and JAK2 (by similarity). Reason: Consistent with IBA and ISO annotations for the same term, and supported by experimental evidence of MuSK interaction (PMID:19038220).
GO:0031072 heat shock protein binding	IEA GO_REF:0000002	ACCEPT	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. 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). Supporting Evidence: PMID:14993262 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 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0042127 regulation of cell population proliferation	IEA GO_REF:0000117	KEEP AS NON CORE	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. Reason: Supported as a tissue-specific downstream consequence of Dnaja3 loss in T cells and fibroblasts, but proliferation regulation is not the primary mitochondrial HSPA9 co-chaperone function. Supporting Evidence: PMID:15879105 the subpopulation of DN4 thymocytes was measurably smaller because of reduced proliferation and significant cell death
GO:0043069 negative regulation of programmed cell death	IEA GO_REF:0000117	KEEP AS NON CORE	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. Reason: Consistent with IMP evidence (PMID:14993262), but programmed-cell-death suppression is a survival phenotype downstream of Dnaja3/HSP70 co-chaperone activity rather than the gene's core molecular function. Supporting Evidence: PMID:14993262 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
GO:0045211 postsynaptic membrane	IEA GO_REF:0000044	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:19038220 Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Metal ion binding is a broad parent of the zinc-binding annotation expected for DnaJ-type cysteine-rich regions. Reason: The more informative annotation is GO:0008270 zinc ion binding; broad metal ion binding is redundant and less specific. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: Unfolded protein binding is not the preferred term for Dnaja3; the supported conserved role is mitochondrial Hsp40 protein-folding chaperone/co-chaperone activity. Reason: GO:0044183 protein folding chaperone captures the DnaJ co-chaperone role more accurately than the vague/proposed-obsolete unfolded-protein-binding term. Proposed replacements: protein folding chaperone Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0000122 negative regulation of transcription by RNA polymerase II	ISO GO_REF:0000119	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15572682 Tid1 contributes to senescence by acting as a repressor of NF-kappaB signaling
GO:0005133 type II interferon receptor binding	ISO GO_REF:0000119	KEEP AS NON CORE	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. 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.
GO:0005634 nucleus	ISO GO_REF:0000119	MODIFY	Summary: ISO annotation for nuclear localization is not supported by the cached local mouse evidence. PMID:11116152 supports cytoplasmic precursor/mitochondrial mature forms and perinuclear mitochondrial membranes, not nuclear localization. Reason: Replace the unsupported nuclear localization with the mitochondrial localization supported by the available evidence. Proposed replacements: mitochondrion
GO:0005737 cytoplasm	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for cytoplasm localization. The precursor form of Dnaja3 is cytoplasmic before mitochondrial import (PMID:11116152). 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). Supporting Evidence: PMID:11116152 both cytoplasmic precursor and mitochondrial mature forms of mTid-1 associate with GAP in vivo
GO:0005739 mitochondrion	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for mitochondrial localization from human ortholog. Extensively supported by multiple experimental annotations in mouse. Reason: Redundant with IBA and multiple experimental (IDA, IMP, HDA) annotations but not incorrect. Well-established core localization. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005759 mitochondrial matrix	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for mitochondrial matrix from human ortholog. Consistent with the transit peptide and known function in mitochondrial matrix. Reason: Supported by protein structure (transit peptide) and functional data showing activity in the mitochondrial matrix (PMID:16327803). Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005829 cytosol	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for cytosol from human ortholog. Also supported by IDA in mouse (PMID:11116152, PMID:19038220). Reason: Consistent with experimental IDA evidence in mouse.
GO:0005884 actin filament	ISO GO_REF:0000119	KEEP AS NON CORE	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. 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.
GO:0006457 protein folding	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for protein folding from human ortholog. Dnaja3 participates in protein folding as a co-chaperone of HSP70 in the mitochondrial matrix. 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. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0007528 neuromuscular junction development	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO annotation from human ortholog for NMJ development. Also supported by direct IMP evidence in mouse (PMID:19038220). 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. Supporting Evidence: PMID:19038220 Tid1 is an essential component of the agrin signaling pathway, crucial for synaptic development
GO:0008285 negative regulation of cell population proliferation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO annotation from human ortholog. Dnaja3/Tid1 suppresses spontaneous immortalization and ectopic expression suppresses cell proliferation (PMID:15572682). 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. Supporting Evidence: PMID:15572682 spontaneous immortalization of rat embryo fibroblasts is suppressed upon ectopic expression of Tid1
GO:0019901 protein kinase binding	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation from human ortholog for protein kinase binding. Consistent with IBA and direct mouse evidence for MuSK interaction (PMID:19038220). Reason: Consistent with multiple lines of evidence including IBA and experimental data.
GO:0030544 Hsp70 protein binding	ISO GO_REF:0000096	ACCEPT	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). Reason: Core function. The J domain of Dnaja3 mediates its essential interaction with HSP70 (HSPA9). This interaction is required for cell survival (PMID:14993262). Supporting Evidence: PMID:14993262 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 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0031398 positive regulation of protein ubiquitination	ISO GO_REF:0000119	REMOVE	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. Reason: No local Dnaja3-specific evidence supports positive regulation of protein ubiquitination. The available evidence supports mitochondrial Hsp70 co-chaperone activity and client protein stabilization, not this transferred BP annotation.
GO:0034341 response to type II interferon	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO annotation from human ortholog. UniProt notes Dnaja3 can modulate IFN-gamma-mediated transcriptional activity (by similarity) and interacts with IFN-gammaR2 chain. Reason: Supported by similarity data from the human ortholog. IFN-gamma signaling modulation is a pleiotropic function of Dnaja3, not its core molecular activity.
GO:0042645 mitochondrial nucleoid	ISO GO_REF:0000119	MODIFY	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. Reason: The Polg client evidence supports mitochondrial matrix proteostasis and mitochondrial DNA maintenance, but does not directly localize Dnaja3 to mitochondrial nucleoids. Replace with the established matrix localization. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:16327803 Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0043065 positive regulation of apoptotic process	ISO GO_REF:0000119	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:11116152 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
GO:0043066 negative regulation of apoptotic process	ISO GO_REF:0000119	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:14993262 Tid1 removal in these cells led to massive cell death
GO:0043124 negative regulation of canonical NF-kappaB signal transduction	ISO GO_REF:0000119	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15572682 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
GO:0044877 protein-containing complex binding	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Protein-containing complex binding is generic and does not add useful information beyond the specific chaperone and partner-binding annotations. Reason: Use Hsp70 protein binding, protein kinase binding, NF-kappaB binding, or protein folding chaperone terms where supported. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md GO:0005515 protein binding and GO:0044877 protein-containing complex binding are too generic
GO:0050821 protein stabilization	ISO GO_REF:0000119	ACCEPT	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. 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). Supporting Evidence: PMID:16327803 Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0051059 NF-kappaB binding	ISO GO_REF:0000119	REMOVE	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. Reason: PMID:15572682 supports Tid1 repression of NF-kappaB signaling, not direct Dnaja3 binding to NF-kappaB transcription factors. The direct binding annotation is not supported by the local evidence. Supporting Evidence: PMID:15572682 NF-kappaB sequence-specific binding is strongly downregulated upon senescence in rat embryo fibroblasts
GO:0060336 negative regulation of type II interferon-mediated signaling pathway	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO annotation from human ortholog. UniProt notes Dnaja3 can modulate IFN-gamma-mediated transcriptional activity (by similarity). 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.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	ISO GO_REF:0000119	REMOVE	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. Reason: The available local evidence supports signaling effects downstream of Dnaja3/Tid1, but not direct binding to RNA polymerase II-specific DNA-binding transcription factors.
GO:0106137 IkappaB kinase complex binding	ISO GO_REF:0000119	REMOVE	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. Reason: NF-kappaB signaling repression does not establish direct Dnaja3 binding to the IkappaB kinase complex. Remove this unsupported transferred binding annotation.
GO:0140297 DNA-binding transcription factor binding	ISO GO_REF:0000119	REMOVE	Summary: ISO annotation from human ortholog. Parent term of GO:0061629. Likely relates to NF-kappaB and IFN-gamma signaling interactions. Reason: This parent binding term inherits the same unsupported direct transcription-factor binding assertion; the local evidence supports signaling regulation, not this molecular interaction.
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara-transferred annotation from human DNAJA3. Duplicates the ISO annotation with the same GO term. Reason: Consistent with ISO annotation. Non-core pleiotropic function related to NF-kappaB signaling regulation (PMID:15572682).
GO:0005739 mitochondrion	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation for mitochondrial localization. Redundant with IBA, ISO, and multiple experimental annotations. Reason: Core localization, consistent with all other evidence. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005884 actin filament	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara-transferred annotation for actin filament co-localization. Duplicates the ISO annotation. Reason: Consistent with ISO annotation. Co-localization qualifier; non-core.
GO:0008285 negative regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara-transferred annotation. Duplicates ISO annotation. Reason: Consistent with ISO and experimental data. Non-core pleiotropic function.
GO:0030544 Hsp70 protein binding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara-transferred Hsp70 protein binding. Core function of DnaJ proteins. Reason: Core function consistent with ISO and fundamental DnaJ biology (PMID:14993262). Supporting Evidence: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0042645 mitochondrial nucleoid	IEA GO_REF:0000107	MODIFY	Summary: Ensembl Compara-transferred mitochondrial nucleoid localization. Consistent with ISO annotation and Polg chaperone function. Reason: Polg client evidence supports mitochondrial DNA maintenance but does not directly localize Dnaja3 to mitochondrial nucleoids. Replace with the established matrix localization. Proposed replacements: mitochondrial matrix Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0009898 cytoplasmic side of plasma membrane	IDA PMID:19038220 A mammalian homolog of Drosophila tumorous imaginal discs, T...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:19038220 Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates
GO:0090398 cellular senescence	IDA PMID:15572682 Functional genetic screen for genes involved in senescence: ...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15572682 Expression of Tid1 is upregulated upon cellular senescence in rat and mouse embryo fibroblasts and premature senescence of REF52 cells triggered by activated ras
GO:0043069 negative regulation of programmed cell death	IMP PMID:14993262 Tid1, a cochaperone of the heat shock 70 protein and the mam...	KEEP AS NON CORE	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. Reason: Strong experimental evidence supports a pro-survival phenotype, because Tid1 removal causes massive cell death rescued by wild-type but not J-domain-mutant Tid1 (PMID:14993262). This should be retained as a non-core consequence of HSP70 co-chaperone activity rather than treated as a primary Dnaja3 function. Supporting Evidence: PMID:14993262 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
GO:0007264 small GTPase-mediated signal transduction	IDA PMID:11116152 A mouse homologue of the Drosophila tumor suppressor l(2)tid...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:11116152 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 PMID:19038220 Tid1 knockdown inhibited AChR clustering, as well as agrin-induced activation of the Rac and Rho small GTPases
GO:0030695 GTPase regulator activity	IDA PMID:11116152 A mouse homologue of the Drosophila tumor suppressor l(2)tid...	MARK AS OVER ANNOTATED	Summary: The RASA1/GAP interaction supports involvement in small GTPase signaling context but does not show that Dnaja3 itself has GTPase regulator activity. Reason: Physical association with a GTPase regulator should not be propagated as Dnaja3 having GTPase regulator molecular activity. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone
GO:0005829 cytosol	IDA PMID:19038220 A mammalian homolog of Drosophila tumorous imaginal discs, T...	ACCEPT	Summary: IDA annotation for cytosol localization from PMID:19038220. Detected in cytosol during NMJ studies. Reason: Valid experimental observation. Consistent with other IDA evidence for cytosol localization (PMID:11116152).
GO:0007528 neuromuscular junction development	IMP PMID:19038220 A mammalian homolog of Drosophila tumorous imaginal discs, T...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:19038220 Knockdown of Tid1 by short hairpin RNA (shRNA) in skeletal muscle fibers dispersed synaptic AChR clusters and impaired neuromuscular transmission
GO:0031594 neuromuscular junction	IDA PMID:19038220 A mammalian homolog of Drosophila tumorous imaginal discs, T...	KEEP AS NON CORE	Summary: IDA annotation for NMJ localization from PMID:19038220. Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates. Reason: Valid experimental observation of tissue-specific localization. Context-dependent localization related to NMJ signaling function, not primary subcellular location. Supporting Evidence: PMID:19038220 Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates
GO:0045211 postsynaptic membrane	IDA PMID:19038220 A mammalian homolog of Drosophila tumorous imaginal discs, T...	KEEP AS NON CORE	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. Reason: Valid experimental observation. Tissue-specific localization at the NMJ, mediated by MuSK interaction (PMID:19038220). Non-core localization. Supporting Evidence: PMID:19038220 Like MuSK, Tid1 colocalizes with AChRs at developing, adult, and denervated motor endplates
GO:0005739 mitochondrion	HDA PMID:18614015 A mitochondrial protein compendium elucidates complex I dise...	ACCEPT	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. Reason: Strong proteomic evidence from the comprehensive MitoCarta study. Consistent with all other evidence for mitochondrial localization. Supporting Evidence: PMID:18614015 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 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005515 protein binding	IPI PMID:14993262 Tid1, a cochaperone of the heat shock 70 protein and the mam...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for Dnaja3 physical-interaction evidence. Reason: The cited interactions are better represented by Hsp70 binding, protein folding chaperone activity, or specific context-dependent partner terms. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md GO:0005515 protein binding and GO:0044877 protein-containing complex binding are too generic
GO:0005515 protein binding	IPI PMID:16327803 A crucial role of mitochondrial Hsp40 in preventing dilated ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for Dnaja3 physical-interaction evidence. Reason: The cited interactions are better represented by Hsp70 binding, protein folding chaperone activity, or specific context-dependent partner terms. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md GO:0005515 protein binding and GO:0044877 protein-containing complex binding are too generic
GO:0005739 mitochondrion	IMP PMID:14993262 Tid1, a cochaperone of the heat shock 70 protein and the mam...	ACCEPT	Summary: IMP annotation for mitochondrial localization from PMID:14993262, based on knockout studies where Tid1 deletion leads to mitochondrial dysfunction. Reason: Consistent with all other evidence for mitochondrial localization. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005739 mitochondrion	IDA PMID:16327803 A crucial role of mitochondrial Hsp40 in preventing dilated ...	ACCEPT	Summary: IDA annotation for mitochondrial localization from PMID:16327803. Dnaja3 is described as "the mitochondrial chaperone Hsp40." Reason: Direct experimental evidence for core localization. Supporting Evidence: PMID:16327803 the mitochondrial chaperone Hsp40, also known as Dnaja3 or Tid1 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0006264 mitochondrial DNA replication	IMP PMID:16327803 A crucial role of mitochondrial Hsp40 in preventing dilated ...	ACCEPT	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. 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. Supporting Evidence: PMID:16327803 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. file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0006915 apoptotic process	IMP PMID:16327803 A crucial role of mitochondrial Hsp40 in preventing dilated ...	KEEP AS NON CORE	Summary: IMP annotation for apoptotic process from PMID:16327803. Cardiac-specific Dnaja3 deletion leads to cardiomyocyte death and dilated cardiomyopathy. Reason: Experimental evidence showing that Dnaja3 loss leads to cardiomyocyte death supports a downstream cell-survival phenotype, not a core molecular function. Supporting Evidence: PMID:16327803 Mice deficient in Dnaja3 developed dilated cardiomyopathy (DCM) and died before 10 weeks of age
GO:0006924 activation-induced cell death of T cells	IMP PMID:15879105 Tid1 is required for T cell transition from double-negative ...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15879105 the subpopulation of DN4 thymocytes was measurably smaller because of reduced proliferation and significant cell death file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md DNAJA3 is required for B cell development, mitochondrial function, and humoral immune output
GO:0007005 mitochondrion organization	IMP PMID:16327803 A crucial role of mitochondrial Hsp40 in preventing dilated ...	ACCEPT	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. Reason: Core function. Strong experimental evidence that Dnaja3 is essential for mitochondrial biogenesis and organization (PMID:16327803). Supporting Evidence: PMID:16327803 Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0033077 T cell differentiation in thymus	IMP PMID:15879105 Tid1 is required for T cell transition from double-negative ...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15879105 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 file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md DNAJA3 is required for B cell development, mitochondrial function, and humoral immune output
GO:0042102 positive regulation of T cell proliferation	IMP PMID:15879105 Tid1 is required for T cell transition from double-negative ...	KEEP AS NON CORE	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. Reason: Valid experimental observation (PMID:15879105). This is a tissue-specific pleiotropic function rather than the core molecular activity. Supporting Evidence: PMID:15879105 the subpopulation of DN4 thymocytes was measurably smaller because of reduced proliferation and significant cell death file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md DNAJA3 is required for B cell development, mitochondrial function, and humoral immune output
GO:0051082 unfolded protein binding	IPI PMID:11116152 A mouse homologue of the Drosophila tumor suppressor l(2)tid...	MODIFY	Summary: Unfolded protein binding is not the preferred term for Dnaja3; the supported conserved role is mitochondrial Hsp40 protein-folding chaperone/co-chaperone activity. Reason: GO:0044183 protein folding chaperone captures the DnaJ co-chaperone role more accurately than the vague/proposed-obsolete unfolded-protein-binding term. Proposed replacements: protein folding chaperone Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005634 nucleus	IDA PMID:11116152 A mouse homologue of the Drosophila tumor suppressor l(2)tid...	MODIFY	Summary: IDA annotation for nuclear localization from PMID:11116152 is not supported by the cached local evidence, which describes cytoplasmic precursor/mitochondrial mature forms and perinuclear mitochondrial membranes. Reason: Replace the unsupported nuclear localization with the mitochondrial localization supported by the available evidence. Proposed replacements: mitochondrion
GO:0005739 mitochondrion	IDA PMID:11116152 A mouse homologue of the Drosophila tumor suppressor l(2)tid...	ACCEPT	Summary: IDA annotation for mitochondrial localization from PMID:11116152. Immunofluorescence showed Tid1 at perinuclear mitochondrial membranes. Reason: Core localization with direct experimental evidence. Supporting Evidence: PMID:11116152 GAP and Tid-1 were shown to colocalize at perinuclear mitochondrial membranes in response to epidermal growth factor stimulation file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins
GO:0005829 cytosol	IDA PMID:11116152 A mouse homologue of the Drosophila tumor suppressor l(2)tid...	ACCEPT	Summary: IDA annotation for cytosol localization from PMID:11116152. The cytoplasmic precursor form of Dnaja3 was detected. Reason: Direct experimental evidence. The precursor form is cytoplasmic before mitochondrial import. Supporting Evidence: PMID:11116152 both cytoplasmic precursor and mitochondrial mature forms of mTid-1 associate with GAP in vivo
GO:0005515 protein binding	IPI PMID:16327803 A crucial role of mitochondrial Hsp40 in preventing dilated ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for Dnaja3 physical-interaction evidence. Reason: The cited interactions are better represented by Hsp70 binding, protein folding chaperone activity, or specific context-dependent partner terms. Supporting Evidence: file:mouse/Dnaja3/Dnaja3-notes.md GO:0005515 protein binding and GO:0044877 protein-containing complex binding are too generic

Core Functions

Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 protein-folding chaperone for the HSPA9/mortalin system, supporting mitochondrial proteostasis, mitochondrial DNA maintenance, and mitochondrial organization.

Molecular Function:

protein folding chaperone

Directly Involved In:

protein folding mitochondrion organization mitochondrial DNA replication

Cellular Locations:

mitochondrial matrix

Supporting Evidence:

file:mouse/Dnaja3/Dnaja3-notes.md
Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone
file:mouse/Dnaja3/Dnaja3-notes.md
Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3
file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000096

Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000119

Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11116152

A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein.

PMID:14993262

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.

PMID:15572682

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.

PMID:15879105

Tid1 is required for T cell transition from double-negative 3 to double-positive stages.

PMID:16327803

A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy.

PMID:18614015

A mitochondrial protein compendium elucidates complex I disease biology.

PMID:19038220

A mammalian homolog of Drosophila tumorous imaginal discs, Tid1, mediates agrin signaling at the neuromuscular junction.

file:mouse/Dnaja3/Dnaja3-notes.md

Dnaja3 curator notes

file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md

Falcon deep research report for mouse Dnaja3

📚 Additional Documentation

Deep Research Falcon

(Dnaja3-deep-research-falcon.md)

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gene_info: Name=Dnaja3; Synonyms=Tid1;
organism_full: Mus musculus (Mouse).
protein_family: Not specified in UniProt
protein_domains: Apopto_cytoskel_mod. (IPR051938); DnaJ. (IPR012724); DnaJ_C. (IPR002939);
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q99M87
Protein Description: RecName: Full=DnaJ homolog subfamily A member 3, mitochondrial; AltName: Full=DnaJ protein Tid-1; Short=mTid-1; AltName: Full=Tumorous imaginal discs protein Tid56 homolog; Flags: Precursor;
Gene Information: Name=Dnaja3; Synonyms=Tid1;
Organism (full): Mus musculus (Mouse).
Protein Family: Not specified in UniProt
Key Domains: Apopto_cytoskel_mod. (IPR051938); DnaJ. (IPR012724); DnaJ_C. (IPR002939); DnaJ_domain. (IPR001623); DnaJ_domain_CS. (IPR018253)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Dnaja3" matches the protein description above
Verify the organism is correct: Mus musculus (Mouse).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'Dnaja3' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene Dnaja3 (gene ID: Dnaja3, UniProt: Q99M87) in mouse.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q99M87
Protein Description: RecName: Full=DnaJ homolog subfamily A member 3, mitochondrial; AltName: Full=DnaJ protein Tid-1; Short=mTid-1; AltName: Full=Tumorous imaginal discs protein Tid56 homolog; Flags: Precursor;
Gene Information: Name=Dnaja3; Synonyms=Tid1;
Organism (full): Mus musculus (Mouse).
Protein Family: Not specified in UniProt
Key Domains: Apopto_cytoskel_mod. (IPR051938); DnaJ. (IPR012724); DnaJ_C. (IPR002939); DnaJ_domain. (IPR001623); DnaJ_domain_CS. (IPR018253)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "Dnaja3" matches the protein description above
Verify the organism is correct: Mus musculus (Mouse).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene Dnaja3 (gene ID: Dnaja3, UniProt: Q99M87) in mouse.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research Report: Mouse Dnaja3 (Tid1) — Functional Annotation and Current Evidence

0) Target verification (critical disambiguation)

The requested target is Mus musculus Dnaja3 (UniProt Q99M87), also called Tid1/TID-1 (tumorous imaginal discs homolog), encoding a mitochondrial DnaJ/Hsp40-family J-domain co-chaperone. Multiple independent sources explicitly define DNAJA3/Tid1 as a mitochondrial co-chaperone that binds mitochondrial Hsp70 (mortalin/HSPA9) through its conserved J domain, consistent with the UniProt description and domain expectations. (banerjee2022puttinghumantid1 pages 1-3, teo2020dnaja3acochaperone pages 1-4)

1) Key concepts and definitions (current understanding)

1.1 What DNAJA3/Tid1 is

DNAJA3 (Tid1) is a J-domain protein (Hsp40) whose core molecular role is to act as a co-chaperone and specificity factor for Hsp70-family chaperones, including mitochondrial Hsp70 (mtHsp70; mortalin/HSPA9). J-domain proteins stimulate Hsp70 ATP hydrolysis, shifting Hsp70 into a high-affinity substrate-binding state and enabling productive folding cycles. (banerjee2022puttinghumantid1 pages 1-3, shin2021lonp1andmthsp70 pages 1-2)

1.2 Subcellular localization and processing

Tid1/DNAJA3 is described as predominantly mitochondrial (matrix-localized after import), synthesized as a precursor and processed after mitochondrial import. The protein has at least two major splice isoforms: Tid1L (~43 kDa) and Tid1S (~40 kDa), differing at the C-terminus and reported to have distinct functional effects in apoptosis-related contexts. In a mouse B-cell conditional knockout study, both long-form (43 kDa) and short-form (40 kDa) species were detected by immunoblot, supporting isoform expression in vivo. (banerjee2022puttinghumantid1 pages 1-3, dong2024apeptidederived pages 1-2, sayson2024dnaja3regulatesb pages 2-3)

1.3 “Primary function” framing for functional annotation

For functional annotation purposes, DNAJA3 is best classified as a mitochondrial proteostasis factor (a co-chaperone): it does not catalyze a chemical reaction as an enzyme, but instead modulates the folding/biogenesis and quality control of mitochondrial proteins by regulating mtHsp70 activity and pathway coupling to other matrix proteostasis factors. (shin2021lonp1andmthsp70 pages 1-2)

2) Molecular mechanism, pathways, and substrates/clients

2.1 mtHsp70 (HSPA9) co-chaperone function during mitochondrial protein biogenesis

A central mechanistic study of mitochondrial matrix proteostasis describes mtHsp70 functioning in sequential complexes: (i) an import motor role at the inner membrane and (ii) a folding role with soluble co-chaperones including DNAJA3 (TID1) and nucleotide exchange factors (e.g., GRPEL1). DNAJA3 is explicitly described as a J-domain co-chaperone that supports the folding function of mtHsp70 by enhancing ATP hydrolysis. (shin2021lonp1andmthsp70 pages 1-2, shin2021lonp1andmthsp70 pages 2-4)

2.2 Functional coupling to LONP1-mediated folding/anti-aggregation activity

A key mechanistic advance is the demonstrated coupling of DNAJA3/mtHsp70 to the mitochondrial AAA+ protease LONP1 acting in a chaperone-like (ATPase-dependent) pathway for folding newly imported proteins.

DNAJA3 knockdown caused strong insolubility/aggregation of mitochondrial proteins such as OXA1L (inner membrane insertase) and NDUFA9 (Complex I subunit), comparable to LONP1 inhibition/knockdown. (shin2021lonp1andmthsp70 pages 2-4, shin2021lonp1andmthsp70 pages 4-6)
Proteomics of detergent-insoluble mitochondrial aggregates showed a high correlation between LONP1 knockdown and DNAJA3 knockdown aggregation profiles (reported correlation coefficient R² ≈ 0.6687), with ~135 mitochondrial proteins aggregated >2-fold (p < 0.05) in both conditions, largely matrix/inner-membrane localized. (shin2021lonp1andmthsp70 pages 4-6)
In vitro reconstitution demonstrated that mtHsp70 plus DNAJA3/GRPEL1 alone was ineffective at solubilizing the challenging substrate OXA1L and tended to become insoluble with OXA1L, whereas inclusion of LONP1 (protease-deficient but ATPase competent) protected chaperone components and improved solubilization, supporting a model where LONP1 provides a critical anti-aggregation/folding support function in the mtHsp70–DNAJA3 pathway. (shin2021lonp1andmthsp70 pages 6-8)

Together, these data position DNAJA3 as a core node in the mitochondrial folding/anti-aggregation network that is especially important during the biogenesis phase of certain mitochondrial proteins (import + early folding intermediates). (shin2021lonp1andmthsp70 pages 2-4, shin2021lonp1andmthsp70 pages 1-2)

2.3 Frataxin (FXN) is a 2024-supported DNAJA3/Tid1 interactor/client axis

A 2024 study in the Friedreich’s ataxia (FRDA) context identifies TID1/DNAJA3 as a binding partner of frataxin (FXN) with functional consequences:

TID1 physically interacts with FXN in vivo in mouse cortex and in vitro in cortical neurons. (dong2024apeptidederived pages 1-2)
TID1 overexpression increased FXN precursor but decreased intermediate/mature FXN, consistent with a role in negative regulation of mature frataxin levels. (dong2024apeptidederived pages 1-2)
Overexpression of TID1S in patient fibroblasts decreased mature FXN and increased mitochondrial fragmentation; a peptide corresponding to the last 6 amino acids of TID1S rescued frataxin deficiency and mitochondrial defects in FRDA patient-derived cells, indicating a tractable, application-facing interface. (dong2024apeptidederived pages 1-2)

This provides a concrete, recent “client/regulatory target” relationship for DNAJA3 beyond general proteostasis. (dong2024apeptidederived pages 1-2)

3) Mouse genetics, tissue function, and quantitative phenotypes

3.1 Developmental essentiality

Reviews and chapters summarizing mouse genetic evidence report that homozygous/global Dnaja3 (Tid1) knockout is early embryonic lethal, with lethality reported between approximately E4.5 and E7.5 or embryos not detected by E7.5, indicating an essential developmental role consistent with a core mitochondrial proteostasis gene. (teo2020dnaja3acochaperone pages 8-11, sayson2024dnaja3regulatesb pages 1-2)

3.2 Skeletal muscle: energy homeostasis and muscular dystrophy phenotypes

A mouse skeletal muscle-specific deletion study (HSA-Cre; Tid1f/f) demonstrates a mitochondrial/energetic role during myogenesis:

HSA-Tid1f/f mice displayed reduced muscle fiber size and dystrophic features; importantly, they died between postnatal day P8 and P10, indicating severe early postnatal dependence on Tid1 in muscle. (cheng2016mitochondrialcochaperoneprotein pages 5-8)
Molecular readouts in muscle showed reduced MyHC (developmental marker), reduced mitochondrial biogenesis marker PGC-1α, altered p-AMPK, and increased apoptotic marker cleaved caspase-3 at P5/P8. (cheng2016mitochondrialcochaperoneprotein pages 1-2, cheng2016mitochondrialcochaperoneprotein pages 5-8)
In vitro, Tid1 knockdown in C2C12 myoblasts reduced mitochondrial mass and membrane potential (MitoTracker/JC-1 staining) and reduced intracellular ATP prior to differentiation, consistent with a role in maintaining mitochondrial activity necessary for differentiation. (cheng2016mitochondrialcochaperoneprotein pages 5-8)

These results support a functional annotation of Dnaja3 as essential for mitochondrial function and ATP homeostasis in muscle differentiation and maintenance. (cheng2016mitochondrialcochaperoneprotein pages 1-2)

3.3 B cells: 2024 conditional KO links DNAJA3 to immunometabolism and OXPHOS integrity

A recent B-cell-specific knockout mouse model (CD19-Cre; DNAJA3flx/flx) directly demonstrates that DNAJA3 is required for B cell development, mitochondrial function, and humoral immune output.

Key quantitative/statistical findings reported:

Immunoblot validation showed DNAJA3 protein expression in sorted CD19+ B cells was reduced by ~66% in KO relative to control. (sayson2024dnaja3regulatesb pages 5-6)
Early B cell development: significant reductions in later stages (Pre-B and immature B) in KO animals (N≈20) with multiple p-values (e.g., immature B reduction p ≤ 0.04). (sayson2024dnaja3regulatesb pages 3-5, sayson2024dnaja3regulatesb pages 5-6)
Peripheral B cell pools: mature B cell numbers decreased markedly in blood and spleen (e.g., immature B cells reduced by ~42.37% in blood; mature B cells reduced by ~47.29% in blood; both with strong significance). (sayson2024dnaja3regulatesb pages 6-9)
Activation and effector outcomes: KO reduced proliferation (CFSE proliferation index difference p = 0.046) and reduced metabolic activity by MTT (OD570 reductions with TI p = 0.041; TD p = 0.034), and significantly reduced plasmablast/plasma cell output and IgM/IgG production (p ≤ 0.0001). (sayson2024dnaja3regulatesb pages 9-11)
Mitochondrial phenotype: KO reduced mitochondrial mass and membrane potential (notably under TD stimulation; e.g., mitochondrial mass p = 0.035, membrane potential p = 0.014), reduced fraction of functional mitochondria and increased dysfunctional mitochondria, and decreased OXPHOS complexes, with particularly strong reductions in Complex I together with Complex II and Complex IV. (sayson2024dnaja3regulatesb pages 9-11, sayson2024dnaja3regulatesb pages 11-14)

Visual evidence for the mitochondrial and OXPHOS findings is presented in Figure 8 of the paper (mitochondrial assays and OXPHOS immunoblots). (sayson2024dnaja3regulatesb media baef7d24, sayson2024dnaja3regulatesb media eeab5ce1)

4) Recent developments (prioritizing 2023–2024) and “latest research” implications

4.1 2024: DNAJA3 expands into immune function as a mitochondrial quality-control determinant

The 2024 B-cell conditional KO study adds recent, in vivo evidence that DNAJA3’s mitochondrial co-chaperone role has direct immunological consequences, linking mitochondrial OXPHOS integrity to B cell development, antigen-dependent activation, and antibody production. This extends DNAJA3 from a broadly described mitostasis factor into a more concretely testable immunometabolic node. (sayson2024dnaja3regulatesb pages 1-2, sayson2024dnaja3regulatesb pages 9-11)

4.2 2024: TID1–frataxin axis and a peptide rescue strategy

The 2024 FRDA study proposes a mechanistic and therapeutic framework where TID1 negatively regulates mature frataxin and where a short TID1S-derived peptide can rescue FRDA patient-cell mitochondrial phenotypes. This positions DNAJA3 not only as a mitochondrial housekeeping co-chaperone but also as a drug-targetable regulator of a disease-limiting mitochondrial protein (FXN). (dong2024apeptidederived pages 1-2)

5) Current applications and real-world implementations

5.1 Mouse models as functional tools

Current “real-world” implementations are primarily conditional mouse models used to interrogate mitochondrial proteostasis in specific tissues:

B cell-specific DNAJA3 KO (CD19-Cre; DNAJA3flx/flx) for studying mitochondrial contributions to B cell development, immunoglobulin production, and antigen-driven activation and mitochondrial functional readouts via flow cytometry (MitoTracker/JC-1) and OXPHOS immunoblotting. (sayson2024dnaja3regulatesb pages 1-2, sayson2024dnaja3regulatesb pages 9-11)
Skeletal muscle-specific Tid1 KO (HSA-Cre; Tid1f/f) as a model linking mitochondrial energetic failure to dystrophic pathology and early postnatal lethality. (cheng2016mitochondrialcochaperoneprotein pages 5-8)

5.2 Therapeutic concept: targeting DNAJA3–FXN regulation

The FRDA study provides an application-facing approach: a TID1S C-terminal hexapeptide that rescues mitochondrial defects in FRDA patient-derived cells, suggesting a concrete path toward therapeutic modulation of DNAJA3-dependent frataxin control. (dong2024apeptidederived pages 1-2)

6) Expert opinions and analysis (authoritative synthesis)

A 2022 comprehensive review emphasizes DNAJA3/Tid1 as a multi-interaction mitochondrial J-protein implicated across proliferation, differentiation, apoptosis, and disease, proposing it as an important therapeutic target and framing its disease links through its interaction network and proteostasis roles. (banerjee2022puttinghumantid1 pages 1-3)

Mechanistic mitochondrial proteostasis work (Nature Communications) supports an expert-level conceptual model in which DNAJA3 functions not in isolation but as part of a coordinated matrix folding system (mtHsp70–DNAJA3–GRPEL) that is functionally intertwined with LONP1’s ATPase-dependent anti-aggregation activity, especially for biogenesis of specific inner membrane/matrix proteins. (shin2021lonp1andmthsp70 pages 1-2, shin2021lonp1andmthsp70 pages 6-8)

7) Evidence summary table

Topic	Key findings	Best supporting source(s) with publication year and URL	PaperQA citation IDs
Identity / synonyms	Mouse Dnaja3 matches UniProt Q99M87 and is the mitochondrial Hsp40/J-protein commonly called Tid1 / mTid-1 / Tid56 homolog. It is a DnaJ-family co-chaperone with a conserved J domain that works with mitochondrial Hsp70.	Banerjee et al., 2022, Cell Communication and Signaling, https://doi.org/10.1186/s12964-022-00912-5; Teo et al., 2020, https://doi.org/10.1007/7515_2020_33	(banerjee2022puttinghumantid1 pages 1-3, teo2020dnaja3acochaperone pages 1-4)
Localization / isoforms	Dnaja3/Tid1 is predominantly imported into the mitochondrial matrix as a precursor and processed after import. Two main isoforms are emphasized: Tid1L (~43 kDa) and Tid1S (~40 kDa), which differ at the C terminus and can show distinct apoptotic effects; in B cells, both long and short forms were detected by immunoblot.	Banerjee et al., 2022, https://doi.org/10.1186/s12964-022-00912-5; Dong et al., 2024, https://doi.org/10.3389/fphar.2024.1352311; Sayson et al., 2024, https://doi.org/10.1016/j.bj.2023.100628	(banerjee2022puttinghumantid1 pages 1-3, dong2024apeptidederived pages 1-2, sayson2024dnaja3regulatesb pages 2-3)
Molecular function	The primary function is as a mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial proteins. DNAJA3 function overlaps mechanistically with the mtHSP70–GRPEL system and intersects with LONP1-dependent protein folding, especially during protein biogenesis rather than after mature folding.	Shin et al., 2021, Nature Communications, https://doi.org/10.1038/s41467-020-20597-z; Banerjee et al., 2022, https://doi.org/10.1186/s12964-022-00912-5	(shin2021lonp1andmthsp70 pages 1-2, shin2021lonp1andmthsp70 pages 2-4, shin2021lonp1andmthsp70 pages 4-6)
Key interactors / clients	Reported interactors/clients include mtHSP70/HSPA9, GRPEL1, LONP1-linked folding substrates such as OXA1L and NDUFA9, and frataxin (FXN). In 2024 work, TID1 was shown to bind FXN in mouse cortex and cultured neurons and to reduce mature frataxin levels when overexpressed, while a TID1S-derived peptide rescued FRDA cellular defects.	Shin et al., 2021, https://doi.org/10.1038/s41467-020-20597-z; Dong et al., 2024, https://doi.org/10.3389/fphar.2024.1352311; Teo et al., 2020, https://doi.org/10.1007/7515_2020_33	(shin2021lonp1andmthsp70 pages 1-2, dong2024apeptidederived pages 1-2, teo2020dnaja3acochaperone pages 11-14)
Mouse phenotypes	Mouse genetic studies indicate that global Dnaja3 loss is early embryonic lethal (reported around E4.5-E7.5). Tissue-specific loss causes strong mitochondrial phenotypes: cardiomyocyte deletion leads to dilated cardiomyopathy, reduced mtDNA copy number, respiratory-chain defects, and death before 10 weeks; skeletal muscle deletion causes muscular dystrophy, reduced ATP/PGC-1α, increased apoptosis, and death around P8-P10; B-cell deletion reduces B-cell development, mitochondrial mass/potential, OXPHOS complexes, proliferation, and antibody production.	Cheng et al., 2016, https://doi.org/10.1186/s13287-016-0443-8; Sayson et al., 2024, https://doi.org/10.1016/j.bj.2023.100628; Teo et al., 2020, https://doi.org/10.1007/7515_2020_33	(cheng2016mitochondrialcochaperoneprotein pages 5-8, cheng2016mitochondrialcochaperoneprotein pages 1-2, sayson2024dnaja3regulatesb pages 5-6, sayson2024dnaja3regulatesb pages 9-11, sayson2024dnaja3regulatesb pages 11-14, teo2020dnaja3acochaperone pages 8-11)
2023-2024 developments / applications	Recent work expands Dnaja3 from a general mitochondrial co-chaperone to a disease-relevant regulator of immune-cell metabolism and frataxin biology. 2024 studies provide two application-facing directions: B cell-specific mouse models for immunometabolic biology and a TID1S-derived rescue peptide as a potential therapeutic lead for Friedreich’s ataxia-related mitochondrial defects.	Sayson et al., 2024, https://doi.org/10.1016/j.bj.2023.100628; Dong et al., 2024, https://doi.org/10.3389/fphar.2024.1352311	(sayson2024dnaja3regulatesb pages 1-2, sayson2024dnaja3regulatesb pages 9-11, sayson2024dnaja3regulatesb pages 11-14, dong2024apeptidederived pages 1-2, sayson2024dnaja3regulatesb media baef7d24)

Table: This table condenses the main evidence base for mouse Dnaja3/Tid1, covering identity, mitochondrial localization and isoforms, mechanism, interactors, mouse phenotypes, and the most relevant 2024 developments. It is useful as a quick-reference scaffold for the full research report.

8) Key references (URLs and publication/availability dates where available)

Sayson SL et al. “DNAJA3 regulates B cell development and immune function.” Biomedical Journal 47(2):100628. Available online 2023-07-23; accepted 2023-07-08; received 2023-06-01. https://doi.org/10.1016/j.bj.2023.100628 (sayson2024dnaja3regulatesb pages 1-2)
Dong YN et al. “A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models.” Frontiers in Pharmacology. Published 2024-03. https://doi.org/10.3389/fphar.2024.1352311 (dong2024apeptidederived pages 1-2)
Shin C-S et al. “LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding.” Nature Communications. Published 2021-01. https://doi.org/10.1038/s41467-020-20597-z (shin2021lonp1andmthsp70 pages 1-2)
Cheng L-H et al. “Mitochondrial co-chaperone protein Tid1 is required for energy homeostasis during skeletal myogenesis.” Stem Cell Research & Therapy. Published 2016-12. https://doi.org/10.1186/s13287-016-0443-8 (cheng2016mitochondrialcochaperoneprotein pages 1-2)
Banerjee S et al. “Putting human Tid-1 in context: an insight into its role in the cell and in different disease states.” Cell Communication and Signaling. Published 2022-07. https://doi.org/10.1186/s12964-022-00912-5 (banerjee2022puttinghumantid1 pages 1-3)
Teo W-H et al. “DNAJA3, a Co-chaperone in Development and Tumorigenesis.” Springer chapter (DOI indicates formal publication route; document year 2020-01). https://doi.org/10.1007/7515_2020_33 (teo2020dnaja3acochaperone pages 1-4)

9) Notes on scope and limitations

This report focuses on mouse Dnaja3/Tid1 and the mitochondrial J-protein co-chaperone role supported by in vivo mouse genetics and mechanistic mitochondrial proteostasis studies. Some widely discussed non-mitochondrial signaling interactions for Tid1 are referenced in reviews/chapters, but the strongest mechanistic and quantitative evidence in the retrieved sources centers on mitochondrial folding/quality control and tissue phenotypes (muscle, B cells) and the newly established FXN regulatory axis (2024). (banerjee2022puttinghumantid1 pages 1-3, dong2024apeptidederived pages 1-2, shin2021lonp1andmthsp70 pages 1-2)

References

(banerjee2022puttinghumantid1 pages 1-3): Sagarika Banerjee, Rupesh Chaturvedi, Anu T. Singh, and Hemant R Kushwaha. Putting human tid-1 in context: an insight into its role in the cell and in different disease states. Cell Communication and Signaling : CCS, Jul 2022. URL: https://doi.org/10.1186/s12964-022-00912-5, doi:10.1186/s12964-022-00912-5. This article has 16 citations.
(teo2020dnaja3acochaperone pages 1-4): Wan-Huai Teo, Yu-Ning Fann, and Jeng-Fan Lo. Dnaja3, a co-chaperone in development and tumorigenesis. ArXiv, pages 1-17, Jan 2020. URL: https://doi.org/10.1007/7515_2020_33, doi:10.1007/7515_2020_33. This article has 2 citations.
(shin2021lonp1andmthsp70 pages 1-2): Chun-Shik Shin, Shuxia Meng, Spiros D. Garbis, Annie Moradian, Robert W. Taylor, Michael J. Sweredoski, Brett Lomenick, and David C. Chan. Lonp1 and mthsp70 cooperate to promote mitochondrial protein folding. Nature Communications, Jan 2021. URL: https://doi.org/10.1038/s41467-020-20597-z, doi:10.1038/s41467-020-20597-z. This article has 145 citations and is from a highest quality peer-reviewed journal.
(dong2024apeptidederived pages 1-2): Yi Na Dong, Lucie Vanessa Ngaba, Jacob An, Miniat W. Adeshina, Nathan Warren, Johnathan Wong, and David R. Lynch. A peptide derived from tid1s rescues frataxin deficiency and mitochondrial defects in frda cellular models. Frontiers in Pharmacology, Mar 2024. URL: https://doi.org/10.3389/fphar.2024.1352311, doi:10.3389/fphar.2024.1352311. This article has 2 citations.
(sayson2024dnaja3regulatesb pages 2-3): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(shin2021lonp1andmthsp70 pages 2-4): Chun-Shik Shin, Shuxia Meng, Spiros D. Garbis, Annie Moradian, Robert W. Taylor, Michael J. Sweredoski, Brett Lomenick, and David C. Chan. Lonp1 and mthsp70 cooperate to promote mitochondrial protein folding. Nature Communications, Jan 2021. URL: https://doi.org/10.1038/s41467-020-20597-z, doi:10.1038/s41467-020-20597-z. This article has 145 citations and is from a highest quality peer-reviewed journal.
(shin2021lonp1andmthsp70 pages 4-6): Chun-Shik Shin, Shuxia Meng, Spiros D. Garbis, Annie Moradian, Robert W. Taylor, Michael J. Sweredoski, Brett Lomenick, and David C. Chan. Lonp1 and mthsp70 cooperate to promote mitochondrial protein folding. Nature Communications, Jan 2021. URL: https://doi.org/10.1038/s41467-020-20597-z, doi:10.1038/s41467-020-20597-z. This article has 145 citations and is from a highest quality peer-reviewed journal.
(shin2021lonp1andmthsp70 pages 6-8): Chun-Shik Shin, Shuxia Meng, Spiros D. Garbis, Annie Moradian, Robert W. Taylor, Michael J. Sweredoski, Brett Lomenick, and David C. Chan. Lonp1 and mthsp70 cooperate to promote mitochondrial protein folding. Nature Communications, Jan 2021. URL: https://doi.org/10.1038/s41467-020-20597-z, doi:10.1038/s41467-020-20597-z. This article has 145 citations and is from a highest quality peer-reviewed journal.
(teo2020dnaja3acochaperone pages 8-11): Wan-Huai Teo, Yu-Ning Fann, and Jeng-Fan Lo. Dnaja3, a co-chaperone in development and tumorigenesis. ArXiv, pages 1-17, Jan 2020. URL: https://doi.org/10.1007/7515_2020_33, doi:10.1007/7515_2020_33. This article has 2 citations.
(sayson2024dnaja3regulatesb pages 1-2): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(cheng2016mitochondrialcochaperoneprotein pages 5-8): Li-Hao Cheng, Kai-Feng Hung, Te-Chang Lee, Chih-Yang Huang, Wen-Ting Chiu, Jeng-Fan Lo, and Tung-Fu Huang. Mitochondrial co-chaperone protein tid1 is required for energy homeostasis during skeletal myogenesis. Stem Cell Research & Therapy, Dec 2016. URL: https://doi.org/10.1186/s13287-016-0443-8, doi:10.1186/s13287-016-0443-8. This article has 23 citations and is from a peer-reviewed journal.
(cheng2016mitochondrialcochaperoneprotein pages 1-2): Li-Hao Cheng, Kai-Feng Hung, Te-Chang Lee, Chih-Yang Huang, Wen-Ting Chiu, Jeng-Fan Lo, and Tung-Fu Huang. Mitochondrial co-chaperone protein tid1 is required for energy homeostasis during skeletal myogenesis. Stem Cell Research & Therapy, Dec 2016. URL: https://doi.org/10.1186/s13287-016-0443-8, doi:10.1186/s13287-016-0443-8. This article has 23 citations and is from a peer-reviewed journal.
(sayson2024dnaja3regulatesb pages 5-6): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(sayson2024dnaja3regulatesb pages 3-5): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(sayson2024dnaja3regulatesb pages 6-9): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(sayson2024dnaja3regulatesb pages 9-11): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(sayson2024dnaja3regulatesb pages 11-14): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(sayson2024dnaja3regulatesb media baef7d24): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(sayson2024dnaja3regulatesb media eeab5ce1): Stephanie L. Sayson, Jia-Ning Fan, Chien-Liang Ku, Jeng-Fan Lo, and Shiu-Huey Chou. Dnaja3 regulates b cell development and immune function. Biomedical Journal, 47:100628, Apr 2024. URL: https://doi.org/10.1016/j.bj.2023.100628, doi:10.1016/j.bj.2023.100628. This article has 15 citations.
(teo2020dnaja3acochaperone pages 11-14): Wan-Huai Teo, Yu-Ning Fann, and Jeng-Fan Lo. Dnaja3, a co-chaperone in development and tumorigenesis. ArXiv, pages 1-17, Jan 2020. URL: https://doi.org/10.1007/7515_2020_33, doi:10.1007/7515_2020_33. This article has 2 citations.

Citations

dong2024apeptidederived pages 1-2
cheng2016mitochondrialcochaperoneprotein pages 5-8
cheng2016mitochondrialcochaperoneprotein pages 1-2
https://doi.org/10.1186/s12964-022-00912-5;
https://doi.org/10.1007/7515_2020_33
https://doi.org/10.3389/fphar.2024.1352311;
https://doi.org/10.1016/j.bj.2023.100628
https://doi.org/10.1038/s41467-020-20597-z;
https://doi.org/10.1186/s12964-022-00912-5
https://doi.org/10.1186/s13287-016-0443-8;
https://doi.org/10.1016/j.bj.2023.100628;
https://doi.org/10.3389/fphar.2024.1352311
https://doi.org/10.1038/s41467-020-20597-z
https://doi.org/10.1186/s13287-016-0443-8
https://doi.org/10.1186/s12964-022-00912-5,
https://doi.org/10.1007/7515_2020_33,
https://doi.org/10.1038/s41467-020-20597-z,
https://doi.org/10.3389/fphar.2024.1352311,
https://doi.org/10.1016/j.bj.2023.100628,
https://doi.org/10.1186/s13287-016-0443-8,

Notes

(Dnaja3-notes.md)

Dnaja3 curation notes

Deep research status: just deep-research-falcon mouse Dnaja3 --fallback perplexity-lite --timeout 60 was first run on 2026-05-03 after the Dnajb11 default run had already shown provider failure. Falcon timed out, and the requested perplexity-lite fallback failed with a 401 insufficient-quota error. Per course correction, just deep-research-falcon mouse Dnaja3 --timeout 1800 --fallback perplexity-lite was then run one gene at a time and succeeded, producing Dnaja3-deep-research-falcon.md.

Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone for HSPA9/mortalin. Its core role is protein folding chaperone activity coupled to mitochondrial proteostasis, mitochondrial DNA maintenance, and mitochondrial organization.

Falcon synthesis: The Falcon report verifies Dnaja3/Tid1 as a predominantly mitochondrial DnaJ/Hsp40 co-chaperone for mtHsp70/HSPA9, emphasizing stimulation of Hsp70 ATP hydrolysis and mitochondrial protein-folding/anti-aggregation functions. It adds strong support for coupling to LONP1-dependent mitochondrial protein folding, with DNAJA3 knockdown causing aggregation of mitochondrial proteins such as OXA1L and NDUFA9, and highlights recent B-cell immunometabolic and frataxin/FXN client-regulatory evidence [file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md].

Embryonic and mitochondrial evidence: The Dnaja3 knockout paper reports that "mTid-1 deficiency results in increased apoptosis and embryonic lethality" and supports mitochondrial localization and survival roles PMID:14993262.

Cardiac mitochondrial evidence: The cardiac conditional knockout paper states that "Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3" PMID:16327803. This directly supports mitochondrial DNA replication/maintenance and mitochondrion organization annotations.

T cell evidence: The T-cell conditional knockout study states that "tid1 is critical in early thymocyte development, especially during transition from the DN3 to double-positive stages" PMID:15879105. This is valid developmental/immune biology but non-core for the gene's conserved molecular function.

MuSK evidence: The neuromuscular-junction paper states that the authors used two-hybrid screens to identify Tid1 as a protein "that binds to the cytoplasmic domain of muscle-specific kinase (MuSK)" PMID:19038220. This supports kinase binding and postsynaptic/NMJ annotations as context-specific.

Curation rule: Dnaja3 should not be annotated as ATP binding solely because it has a DnaJ domain; DnaJ proteins stimulate the ATPase cycle of Hsp70 partners. GO:0005515 protein binding and GO:0044877 protein-containing complex binding are too generic when Hsp70 binding or protein folding chaperone function is available.

📄 View Raw YAML

id: Q99M87
gene_symbol: Dnaja3
product_type: PROTEIN
status: COMPLETE
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.
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: KEEP_AS_NON_CORE
    reason: >-
      This broad immune-system umbrella is compatible with tissue-specific T/B-cell phenotypes,
      but it is downstream of the mitochondrial Hsp70 co-chaperone role and should not be retained
      as a core function.
    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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: DNAJA3 is required for B cell development, mitochondrial function, and
        humoral immune output
- 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: KEEP_AS_NON_CORE
    reason: >-
      Broad IEA consistent with tissue-specific immune phenotypes and NF-kappaB signaling
      regulation, but this is downstream/pleiotropic biology rather than the core mitochondrial
      co-chaperone function.
    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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: DNAJA3 is required for B cell development, mitochondrial function, and
        humoral immune output
- 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: ATP binding is not supported for Dnaja3 itself. DnaJ/Hsp40 proteins stimulate ATP
      cycling on Hsp70 partners rather than acting as ATP-binding enzymes.
    action: REMOVE
    reason: This is a domain-transfer overannotation from DnaJ/Hsp40 family context; the ATPase
      belongs to the Hsp70 partner, not Dnaja3.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: Dnaja3 should not be annotated as ATP binding solely because it has a DnaJ
        domain
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA-predicted nuclear localization is not supported by the cached local evidence.
      PMID:11116152 supports cytoplasmic precursor/mitochondrial mature forms and perinuclear
      mitochondrial membranes, not nuclear localization.
    action: MODIFY
    reason: >-
      Replace the unsupported nuclear localization with the mitochondrial localization supported by
      the available evidence.
    proposed_replacement_terms:
    - id: GO:0005739
      label: mitochondrion
    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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: KEEP_AS_NON_CORE
    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: MARK_AS_OVER_ANNOTATED
    reason: >-
      This broad stress-response IEA is inferred from DnaJ/HSP40 family context and lacks
      Dnaja3-specific local support as a core function.
- 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: MARK_AS_OVER_ANNOTATED
    reason: >-
      This heat-response annotation is based on DnaJ domain membership, but local evidence supports
      mitochondrial Hsp70 co-chaperone activity rather than a Dnaja3-specific heat-response role.
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        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: KEEP_AS_NON_CORE
    reason: >-
      Supported as a tissue-specific downstream consequence of Dnaja3 loss in T cells
      and fibroblasts, but proliferation regulation is not the primary mitochondrial
      HSPA9 co-chaperone function.
    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: KEEP_AS_NON_CORE
    reason: >-
      Consistent with IMP evidence (PMID:14993262), but programmed-cell-death suppression
      is a survival phenotype downstream of Dnaja3/HSP70 co-chaperone activity rather than
      the gene's core molecular function.
    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: Metal ion binding is a broad parent of the zinc-binding annotation expected for
      DnaJ-type cysteine-rich regions.
    action: MARK_AS_OVER_ANNOTATED
    reason: The more informative annotation is GO:0008270 zinc ion binding; broad metal ion binding
      is redundant and less specific.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: 'Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone'
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Unfolded protein binding is not the preferred term for Dnaja3; the supported conserved
      role is mitochondrial Hsp40 protein-folding chaperone/co-chaperone activity.
    action: MODIFY
    reason: GO:0044183 protein folding chaperone captures the DnaJ co-chaperone role more accurately
      than the vague/proposed-obsolete unfolded-protein-binding term.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: 'Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone'
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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 is not supported by the cached local mouse evidence.
      PMID:11116152 supports cytoplasmic precursor/mitochondrial mature forms and perinuclear
      mitochondrial membranes, not nuclear localization.
    action: MODIFY
    reason: >-
      Replace the unsupported nuclear localization with the mitochondrial localization supported by
      the available evidence.
    proposed_replacement_terms:
    - id: GO:0005739
      label: mitochondrion
- 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.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: Progressive respiratory chain deficiency and decreased copy number of
        mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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).
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: Progressive respiratory chain deficiency and decreased copy number of
        mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: REMOVE
    reason: >-
      No local Dnaja3-specific evidence supports positive regulation of protein
      ubiquitination. The available evidence supports mitochondrial Hsp70 co-chaperone
      activity and client protein stabilization, not this transferred BP annotation.
- 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: MODIFY
    reason: >-
      The Polg client evidence supports mitochondrial matrix proteostasis and mitochondrial
      DNA maintenance, but does not directly localize Dnaja3 to mitochondrial nucleoids.
      Replace with the established matrix localization.
    proposed_replacement_terms:
    - id: GO:0005759
      label: mitochondrial matrix
    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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: Protein-containing complex binding is generic and does not add useful information
      beyond the specific chaperone and partner-binding annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Use Hsp70 protein binding, protein kinase binding, NF-kappaB binding, or protein folding
      chaperone terms where supported.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: GO:0005515 protein binding and GO:0044877 protein-containing complex binding
        are too generic
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: REMOVE
    reason: >-
      PMID:15572682 supports Tid1 repression of NF-kappaB signaling, not direct Dnaja3
      binding to NF-kappaB transcription factors. The direct binding annotation is not
      supported by the local evidence.
    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: REMOVE
    reason: >-
      The available local evidence supports signaling effects downstream of Dnaja3/Tid1,
      but not direct binding to RNA polymerase II-specific DNA-binding transcription
      factors.
- 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: REMOVE
    reason: >-
      NF-kappaB signaling repression does not establish direct Dnaja3 binding to the
      IkappaB kinase complex. Remove this unsupported transferred binding annotation.
- 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: REMOVE
    reason: >-
      This parent binding term inherits the same unsupported direct transcription-factor
      binding assertion; the local evidence supports signaling regulation, not this
      molecular interaction.
# ============================
# 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.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: Progressive respiratory chain deficiency and decreased copy number of
        mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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).
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: MODIFY
    reason: >-
      Polg client evidence supports mitochondrial DNA maintenance but does not directly
      localize Dnaja3 to mitochondrial nucleoids. Replace with the established matrix
      localization.
    proposed_replacement_terms:
    - id: GO:0005759
      label: mitochondrial matrix
# ============================
# Experimental annotations (IDA, IMP, IPI, HDA) (22)
# ============================
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: Progressive respiratory chain deficiency and decreased copy number of
        mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: KEEP_AS_NON_CORE
    reason: >-
      Strong experimental evidence supports a pro-survival phenotype, because Tid1
      removal causes massive cell death rescued by wild-type but not J-domain-mutant
      Tid1 (PMID:14993262). This should be retained as a non-core consequence of
      HSP70 co-chaperone activity rather than treated as a primary Dnaja3 function.
    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: The RASA1/GAP interaction supports involvement in small GTPase signaling context but
      does not show that Dnaja3 itself has GTPase regulator activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Physical association with a GTPase regulator should not be propagated as Dnaja3 having
      GTPase regulator molecular activity.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: 'Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone'
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14993262
  review:
    summary: Protein binding is too generic for Dnaja3 physical-interaction evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited interactions are better represented by Hsp70 binding, protein folding
      chaperone activity, or specific context-dependent partner terms.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: GO:0005515 protein binding and GO:0044877 protein-containing complex binding
        are too generic
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16327803
  review:
    summary: Protein binding is too generic for Dnaja3 physical-interaction evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited interactions are better represented by Hsp70 binding, protein folding
      chaperone activity, or specific context-dependent partner terms.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: GO:0005515 protein binding and GO:0044877 protein-containing complex binding
        are too generic
- 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.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: Progressive respiratory chain deficiency and decreased copy number of
        mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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.
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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: KEEP_AS_NON_CORE
    reason: >-
      Experimental evidence showing that Dnaja3 loss leads to cardiomyocyte death supports a
      downstream cell-survival phenotype, not a core molecular function.
    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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: DNAJA3 is required for B cell development, mitochondrial function, and
        humoral immune output
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: DNAJA3 is required for B cell development, mitochondrial function, and
        humoral immune output
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: DNAJA3 is required for B cell development, mitochondrial function, and
        humoral immune output
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IPI
  original_reference_id: PMID:11116152
  review:
    summary: Unfolded protein binding is not the preferred term for Dnaja3; the supported conserved
      role is mitochondrial Hsp40 protein-folding chaperone/co-chaperone activity.
    action: MODIFY
    reason: GO:0044183 protein folding chaperone captures the DnaJ co-chaperone role more accurately
      than the vague/proposed-obsolete unfolded-protein-binding term.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: 'Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone'
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11116152
  review:
    summary: >-
      IDA annotation for nuclear localization from PMID:11116152 is not supported by the cached
      local evidence, which describes cytoplasmic precursor/mitochondrial mature forms and
      perinuclear mitochondrial membranes.
    action: MODIFY
    reason: >-
      Replace the unsupported nuclear localization with the mitochondrial localization supported by
      the available evidence.
    proposed_replacement_terms:
    - id: GO:0005739
      label: mitochondrion
- 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
    - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
      supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
        Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
        proteins
- 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
# ============================
# Additional PMID:16327803 protein-binding IPI row with a distinct interactor
# ============================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16327803
  review:
    summary: Protein binding is too generic for Dnaja3 physical-interaction evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited interactions are better represented by Hsp70 binding, protein folding
      chaperone activity, or specific context-dependent partner terms.
    supported_by:
    - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
      supporting_text: GO:0005515 protein binding and GO:0044877 protein-containing complex binding
        are too generic
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: []
- id: file:mouse/Dnaja3/Dnaja3-notes.md
  title: Dnaja3 curator notes
  findings: []
- id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
  title: Falcon deep research report for mouse Dnaja3
  findings: []
core_functions:
- description: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 protein-folding chaperone for the
    HSPA9/mortalin system, supporting mitochondrial proteostasis, mitochondrial DNA maintenance, and
    mitochondrial organization.
  supported_by:
  - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
    supporting_text: 'Core evidence: Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 co-chaperone'
  - reference_id: file:mouse/Dnaja3/Dnaja3-notes.md
    supporting_text: Progressive respiratory chain deficiency and decreased copy number of
      mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3
  - reference_id: file:mouse/Dnaja3/Dnaja3-deep-research-falcon.md
    supporting_text: mitochondrial J-domain co-chaperone for mtHSP70/HSPA9 (mortalin), stimulating
      Hsp70 ATPase activity and promoting folding/quality control of newly imported mitochondrial
      proteins
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  - id: GO:0007005
    label: mitochondrion organization
  - id: GO:0006264
    label: mitochondrial DNA replication
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []

Dnaja3

Gene Description

Existing Annotations Review

Core Functions

Dnaja3/Tid1 is a mitochondrial DnaJ/Hsp40 protein-folding chaperone for the HSPA9/mortalin system, supporting mitochondrial proteostasis, mitochondrial DNA maintenance, and mitochondrial organization.

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Research Report: Mouse Dnaja3 (Tid1) — Functional Annotation and Current Evidence

0) Target verification (critical disambiguation)

1) Key concepts and definitions (current understanding)

1.1 What DNAJA3/Tid1 is

1.2 Subcellular localization and processing

1.3 “Primary function” framing for functional annotation

2) Molecular mechanism, pathways, and substrates/clients

2.1 mtHsp70 (HSPA9) co-chaperone function during mitochondrial protein biogenesis

2.2 Functional coupling to LONP1-mediated folding/anti-aggregation activity

2.3 Frataxin (FXN) is a 2024-supported DNAJA3/Tid1 interactor/client axis

3) Mouse genetics, tissue function, and quantitative phenotypes

3.1 Developmental essentiality

3.2 Skeletal muscle: energy homeostasis and muscular dystrophy phenotypes

3.3 B cells: 2024 conditional KO links DNAJA3 to immunometabolism and OXPHOS integrity

4) Recent developments (prioritizing 2023–2024) and “latest research” implications

4.1 2024: DNAJA3 expands into immune function as a mitochondrial quality-control determinant

4.2 2024: TID1–frataxin axis and a peptide rescue strategy

5) Current applications and real-world implementations

5.1 Mouse models as functional tools

5.2 Therapeutic concept: targeting DNAJA3–FXN regulation

6) Expert opinions and analysis (authoritative synthesis)

7) Evidence summary table

8) Key references (URLs and publication/availability dates where available)

9) Notes on scope and limitations

Citations

Notes

Dnaja3 curation notes

📄 View Raw YAML