Dnaja3

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

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

Deep Research

Falcon

📚 Additional Documentation

Notes

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