Affinage

DNAJA3

DnaJ homolog subfamily A member 3, mitochondrial · UniProt Q96EY1

Length
480 aa
Mass
52.5 kDa
Annotated
2026-06-09
71 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAJA3 (TID1/hTid-1) is a DnaJ/Hsp40 co-chaperone that pairs its J domain with Hsp70-family chaperones to control client protein fate, mitochondrial integrity, and apoptotic signaling (PMID:10411904, PMID:14993262, PMID:21811887). The gene produces two alternatively spliced matrix-targeted isoforms, hTid-1(L) and hTid-1(S), that both bind mitochondrial Hsp70 and exert opposing effects on apoptosis in a J-domain-dependent manner, with the longer isoform showing extended cytosolic residency conferred by a unique C-terminal domain that engages cytosolic Hsc70 and STAT transcription factors (PMID:10411904, PMID:16531398). With mitochondrial Hsp70/mortalin and the nucleotide exchange factor Mge1, Tid1 reconstitutes ATP-dependent protein disaggregation activity, and a disease-associated p.(Arg151Thr) variant linked to developmental delay and polyneuropathy compromises this chaperone activity to a degree comparable to a catalytically dead HPD-domain mutant (PMID:21811887, PMID:30770860). This chaperone function underlies essential roles in cell survival, demonstrated by embryonic lethality of Tid1-null mice and Hsp70-binding-dependent rescue of cell death (PMID:14993262), thymocyte survival via Bcl-2 (PMID:15879105), and maintenance of mitochondrial membrane potential, mtDNA, and complex I stability through the J domain (PMID:24492964). In the cytosol, Tid1 directs clients toward degradation or relocalization: it counteracts HSP90 stabilization of EGFR to drive its ubiquitination and proteasomal degradation (PMID:23698466), promotes ubiquitin-dependent turnover of Galectin-7 (PMID:30083263), suppresses ErbB-2 expression and downstream ERK/BMK1 signaling (PMID:15520177), and forms a complex with p53 to drive its mitochondrial translocation and transcription-independent apoptosis (PMID:19935715, PMID:21311096). Tid1 is a J-domain-dependent negative regulator of NF-κB, binding the IκB/IKK complex to suppress IKK activity, stabilize IκB, and limit NF-κB-dependent IL-8 transcription and cell motility (PMID:11927590, PMID:15601829, PMID:16204048). It additionally modulates receptor tyrosine kinase signaling at Trk, c-Met, and the agrin-MuSK axis of the neuromuscular junction, where it is required for AChR clustering via Rac/Rho GTPase activation (PMID:15753086, PMID:21242965, PMID:19038220), and when overexpressed drives Drp1-dependent mitochondrial fission (PMID:22595283).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established that TID1 encodes two mitochondrial Hsp70-binding isoforms with opposing, J-domain-dependent effects on apoptosis, defining the gene as a co-chaperone with isoform-specific regulatory output.

    Evidence Co-IP and overexpression of wild-type versus J-domain mutant isoforms with apoptosis assays

    PMID:10411904

    Open questions at the time
    • Did not define the molecular clients whose folding/fate the isoforms control
    • Mechanism of opposing isoform activity not resolved at substrate level
  2. 2001 High

    Showed Tid1 binds active Trk-family and Jak2 kinases and the IFN-γ receptor, positioning the co-chaperone as a modulator of receptor/cytokine signaling complexes.

    Evidence Yeast two-hybrid, endogenous Co-IP, chimeric kinase domain constructs, and transcriptional reporter assays

    PMID:11679576

    Open questions at the time
    • Whether Hsp70 recruitment is required for kinase modulation not established
    • Functional consequence on IFN-γ output mechanistically incomplete
  3. 2002 High

    Defined Tid1 as a J-domain-dependent suppressor of NF-κB by inhibiting IKKβ-mediated IκB phosphorylation, prolonging IκB half-life.

    Evidence Kinase assays, NF-κB reporter assays, IκB stability assays, and J-domain mutant constructs

    PMID:11927590

    Open questions at the time
    • How the J domain mechanistically suppresses IKK activity not resolved
    • Did not identify the chaperone client within the IKK complex
  4. 2004 High

    Demonstrated that Tid1's Hsp70 interaction is essential for organismal and cellular survival, anchoring the chaperone function to viability.

    Evidence Conditional knockout mice with embryonic lethality and cell-death rescue using wild-type versus J-domain mutant constructs

    PMID:14993262

    Open questions at the time
    • The specific survival-critical clients were not identified
    • Tissue-level requirements beyond MEFs not dissected here
  5. 2005 High

    Extended the NF-κB model by showing direct association with the IκB/IKK complex and linked Tid1 loss to NF-κB-driven IL-8 transcription and cancer cell motility, and established a survival role in thymocytes via Bcl-2.

    Evidence Direct binding and IKK activity assays, siRNA knockdown with promoter mutation and neutralizing antibody, plus T-cell conditional KO with Bcl-2 transgenic rescue

    PMID:15601829 PMID:15879105 PMID:16204048

    Open questions at the time
    • Mechanistic basis for cytoplasmic retention of IκB by Tid1 not fully defined
    • Connection between mitochondrial and cytosolic functions left open
  6. 2005 High

    Identified RTK and developmental signaling clients (Trk, ErbB-2, HIF-1α/pVHL), showing Tid1 can both promote neurite outgrowth and suppress oncogenic receptor signaling and angiogenesis.

    Evidence Yeast two-hybrid, Co-IP in primary neurons with phosphorylation mapping, domain mutants, stability and angiogenesis assays

    PMID:15520177 PMID:15753086 PMID:15805242

    Open questions at the time
    • Context-dependence of pro- versus anti-signaling outcomes not unified
    • Direct enzymatic role of the J domain in client degradation not shown
  7. 2006 High

    Resolved the isoform divergence mechanism: a unique Tid1-L C-terminal domain mediates cytosolic Hsc70/STAT binding and prolonged residency, while both isoforms localize to mitochondrial nucleoids and functionally substitute for yeast Mdj1p.

    Evidence Subcellular fractionation, FRAP imaging, Co-IP, yeast complementation, domain deletion, and pulse-chase stability assays

    PMID:16531398

    Open questions at the time
    • Functional role of nucleoid localization not mechanistically tied to a phenotype here
    • How cytosolic residency dictates client selection not fully resolved
  8. 2009 High

    Showed Tid1 forms a p53 complex and drives transcription-independent mitochondrial apoptosis, requiring both the mitochondrial targeting sequence and J domain.

    Evidence Co-IP, fractionation, siRNA and overexpression with domain deletion mutants, and apoptosis assays; direct binding confirmed by far-western with domain mapping

    PMID:19935715 PMID:21311096

    Open questions at the time
    • How the J domain couples p53 to the mitochondrial import machinery not detailed
    • Relationship to Hsp70-dependent disaggregation activity unresolved
  9. 2011 High

    Provided the biochemical core: reconstituted ATP-dependent disaggregation by mortalin with either Tid1 isoform plus Mge1, defining the canonical chaperone activity, while a separate study placed Tid1-S as a c-Met activator.

    Evidence In vitro reconstitution with purified mortalin, Tid1-L/S, and Mge1; Co-IP and kinase/migration assays for c-Met

    PMID:21242965 PMID:21811887

    Open questions at the time
    • Substrate spectrum of the disaggregase in vivo not mapped
    • How the same J-domain activity yields opposite signaling outcomes across receptors unclear
  10. 2013 High

    Established a degradation-directing role: Tid1-L engages EGFR/HSP70/HSP90 to counteract HSP90 stabilization, driving EGFR ubiquitination and proteasomal turnover, with a later study showing Tid1-S instead routes EGFR into mitochondria.

    Evidence Co-IP with domain mapping, ubiquitination assays, knockdown/overexpression, xenografts; and subcellular fractionation with DnaJ mutants for mitochondrial transport

    PMID:23698466 PMID:28714950

    Open questions at the time
    • Determinants selecting degradation versus mitochondrial import of EGFR not defined
    • Whether the two fates are mutually exclusive within a cell unknown
  11. 2012 High

    Connected Tid1 chaperone activity to mitochondrial dynamics, showing dysregulation triggers Drp1-dependent fission via a specific J-domain ATPase-coupling residue.

    Evidence Overexpression, knockdown, H121Q point mutant, live-cell imaging, and Drp1-KO rescue with family-member specificity controls

    PMID:22595283

    Open questions at the time
    • Whether fission reflects a physiological or stress-overexpression response not settled
    • Link between fission and disaggregation activity not established
  12. 2014 High

    Defined the bioenergetic role: Tid1 J-domain activity maintains membrane potential homogeneity, mtDNA, and complex I assembly, preventing complex I aggregation.

    Evidence RNAi with J-domain rescue, membrane potential and oxygen consumption assays, mtDNA quantification, and blue-native PAGE for complex I

    PMID:24492964

    Open questions at the time
    • Whether complex I subunits are direct disaggregase substrates not proven
    • Mechanism linking aggregation to focal Δψ accumulation incomplete
  13. 2018 Medium

    Broadened the degradation-directing repertoire to Galectin-7 and (with lower confidence) Gαs via CHIP, reinforcing Tid1 as a routing factor for client ubiquitination.

    Evidence Affinity chromatography/MS, Co-IP, ubiquitination assays, localization imaging, and tissue-specific KO; CHIP/Gαs study by Co-IP and overexpression only

    PMID:30083263 PMID:30443176

    Open questions at the time
    • Gαs/CHIP findings rest on Co-IP and overexpression without domain mutagenesis
    • Whether Galectin-7 turnover requires Hsp70 cooperation not tested
  14. 2019 High

    Identified the specific cytosolic Hsp70 partners (HSPA1A, HSPA8), reinforced J-domain-dependent NF-κB control in immunity, and revealed antiviral roles routing viral proteins to lysosomal degradation while restoring IFN signaling.

    Evidence Co-IP with HSP70 inhibition and Drosophila genetic validation for NF-κB; Co-IP, domain mapping, KO cells, LC3 interaction, and IFN-β/IRF3 assays for FMDV VP1; in vitro import/disaggregation assays for the R151T disease variant

    PMID:30770860 PMID:30996089 PMID:31005254

    Open questions at the time
    • How a single co-chaperone toggles between proteasomal and lysosomal client routing unresolved
    • Disease variant phenotype not yet mechanistically tied to a specific tissue substrate
  15. 2022 Medium

    Provided structural insight, with NMR showing the Tid1 J-domain/GF-motif resembles the DNAJB subfamily, implying a DNAJB-like mode of allosteric mortalin regulation.

    Evidence Solution NMR spectroscopy of the J-domain and GF-motif with sequence analysis

    PMID:35651334

    Open questions at the time
    • No functional mutagenesis tied the DNAJB-like conformation to activity
    • Full-length structure and client-bound states not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single co-chaperone selects between disaggregation, proteasomal degradation, lysosomal targeting, and mitochondrial import of its many clients, and how isoform identity and cytosolic versus mitochondrial residency dictate this choice, remains unresolved.
  • No unifying model links client routing decisions to isoform or compartment
  • Comprehensive in vivo substrate catalog of the mortalin/Tid1 disaggregase is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0044183 protein folding chaperone 2
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 3 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 2
Partners
EGFRHSPA1AHSPA8HSPA9IKBKBMUSKTP53VHL
Complex memberships
Beclin1-PI3K class III complexIKK/IκB/NF-κB complexmitochondrial nucleoidmortalin (mtHsp70)/Tid1/Mge1 disaggregase

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TID1 encodes two alternatively spliced mitochondrial matrix proteins, hTid-1(L) and hTid-1(S), both of which co-immunoprecipitate with mitochondrial Hsp70. They have opposing effects on apoptosis: hTid-1(L) promotes apoptosis induced by mitomycin C and TNFα in a J-domain-dependent manner, while hTid-1(S) suppresses apoptosis. A J-domain mutant of hTid-1(L) dominantly suppresses apoptosis, and a J-domain mutant of hTid-1(S) increases apoptosis. Co-immunoprecipitation, overexpression of wild-type and J-domain mutant constructs, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 10411904
1998 hTid-1 interacts with the HPV-16 E7 oncoprotein via E7's carboxyl-terminal cysteine-rich metal-binding domain, as determined by yeast two-hybrid screening and complex formation assays. Yeast two-hybrid screen, in vitro complex formation Virology Medium 9683573
2001 hTid-1 interacts with Jak2 (confirmed by co-immunoprecipitation from COS-1 cells and with endogenous proteins in HEp2 cells) and with the IFN-γ receptor subunit IFN-γR2. hTid-1 binds preferentially to active Jak2 kinase domain and both hTid-1 isoforms and Jak2 interact with Hsp70/Hsc70 in vivo; this interaction is reduced after IFN-γ treatment. Both hTid-1(S) and hTid-1(L) modulate IFN-γ-mediated transcriptional activity. Yeast two-hybrid, co-immunoprecipitation (including endogenous proteins), chimeric kinase domain constructs, transcriptional reporter assays The Journal of biological chemistry High 11679576
2001 HTLV-1 Tax interacts with hTid-1 via the central cysteine-rich domain of hTid-1, while hTid-1's J domain mediates its binding to Hsp70. Tax associates with the hTid-1/Hsp70 molecular chaperone complex and alters cellular localization of hTid-1 and Hsp70, sequestering them from perinuclear mitochondrial clusters to a cytoplasmic 'hot spot' structure. hTid-1 expression inhibits the transformation phenotype of lung adenocarcinoma cells. Co-immunoprecipitation, domain-mapping, confocal microscopy for subcellular localization, transformation assays Current biology : CB Medium 11719219
2002 hTid-1 represses NF-κB activity induced by Tax, TNFα, and Bcl10 by suppressing IKKβ-mediated serine phosphorylation of IκBα, requiring a functional J domain. This interaction prolongs the half-life of IκBα and IκBβ. hTid-1 does not affect activity of p38, ERK2, or JNK1. Co-immunoprecipitation, kinase assays, NF-κB reporter assays, J-domain mutant constructs, IκBα stability assays The Journal of biological chemistry High 11927590
2002 hTid-1 interacts with the HSV-1 origin-binding protein UL9 (confirmed by in vitro immunoprecipitation), enhances UL9 binding to the HSV-1 origin oriS, and facilitates multimerization of dimeric UL9 protein, as shown by EMSA. hTid-1 has no effect on UL9's DNA-dependent ATPase or helicase activities. In vitro co-immunoprecipitation, electrophoretic mobility shift assay (EMSA), ATPase and helicase activity assays Proceedings of the National Academy of Sciences of the United States of America Medium 11854491
2004 Tid1 interacts with the cytoplasmic domain of ErbB-2/HER-2. Increased expression of Tid1 in ErbB-2-overexpressing mammary carcinoma cells suppresses ErbB-2 expression levels and attenuates ErbB-2-dependent ERK1/2 and BMK1 signaling, leading to programmed cell death. A functional DnaJ domain is required for this suppression of ErbB-2 expression and signaling. Co-immunoprecipitation, overexpression, DnaJ domain mutant constructs, Western blotting for signaling pathway components, tumor progression assays in animals Cancer research Medium 15520177
2004 Embryonic lethality occurs between E4.5 and E7.5 in Tid1-null mice. In mouse embryonic fibroblasts, Tid1 removal causes massive cell death that is rescued by wild-type Tid1 but not by a J-domain mutant incapable of binding Hsp70, establishing that Tid1's essential role in cell survival requires its interaction with Hsp70. Conditional knockout mouse model, cell death assays, rescue with wild-type vs. J-domain mutant constructs Molecular and cellular biology High 14993262
2005 hTid-1 strongly associates with the cytoplasmic NF-κB-IκB complex through direct interactions with IκBα/β and the IKKα/β subunits of the IKK complex, suppressing IKK activity in a J-domain-dependent manner and causing cytoplasmic retention and enhanced stability of IκB proteins. Co-immunoprecipitation, direct binding assays, IKK activity assays, J-domain deletion mutant, NF-κB reporter assays, tumor growth in nude mice Molecular and cellular biology High 15601829
2005 Tid1 depletion in MDA-MB231 breast cancer cells enhances migration and IL-8 secretion (~3.5-fold). The enhanced migration is blocked by reducing IL-8 expression or adding an IL-8 neutralizing antibody. The IL-8 promoter NF-κB binding site is required for Tid1 depletion-induced IL-8 upregulation, indicating Tid1 negatively regulates cell motility through NF-κB-dependent IL-8 transcription. siRNA knockdown, microarray, ELISA, neutralizing antibody, promoter mutation, migration assay, in vivo metastasis model Cancer research High 16204048
2005 Tid-1(L) directly interacts with pVHL (confirmed in vitro and in vivo), enhances the HIF-1α/pVHL interaction leading to destabilization of HIF-1α protein, thereby decreasing VEGF expression and inhibiting angiogenesis in vitro and in vivo. Yeast two-hybrid, co-immunoprecipitation (in vitro and in vivo), HIF-1α stability assays, VEGF expression assay, in vivo angiogenesis assay Cancer research Medium 15805242
2005 TID1 associates with Trk receptor tyrosine kinases at the kinase activation loop. TID1 is tyrosine phosphorylated by Trk both in yeast and transfected cells, and endogenous TID1 is co-immunoprecipitated with and tyrosine-phosphorylated by Trk in neurotrophin-stimulated primary hippocampal neurons. Both TID1(L) and TID1(S) facilitate NGF-induced neurite outgrowth through a mechanism involving increased MAPK activation; shRNA knockdown of TID1 reduces NGF-induced neurite growth. Yeast two-hybrid, binding assays, co-immunoprecipitation, tyrosine phosphorylation assays in transfected cells and primary neurons, shRNA knockdown, neurite outgrowth assays The Journal of biological chemistry High 15753086
2006 Tid1-L and Tid1-S form heterocomplexes; both isoforms localize to mitochondrial nucleoids (large protein-DNA complexes bound to mtDNA). Tid1-L has a longer cytosolic residency time and greater stability than Tid1-S prior to mitochondrial import; Tid1-S is rapidly degraded in the cytosol. The unique C-terminal domain of Tid1-L is required for interaction with cytosolic Hsc70 and the STAT1 and STAT3 transcription factors, which explains its longer cytosolic half-life. Tid1 functionally substitutes for the yeast mitochondrial DnaJ-like protein Mdj1p. Subcellular fractionation, live-cell imaging/FRAP, co-immunoprecipitation, yeast complementation assay, domain deletion mutants, pulse-chase stability assays The Journal of biological chemistry High 16531398
2005 Tid1 is required for T cell transition from the DN3 to double-positive stage. Tid1-deficient thymocytes show reduced DN4 proliferation and significant cell death with reduced Bcl-2 expression. Restoration of Bcl-2 expression by transgenic human bcl-2 reverses the developmental defect in Tid1-null thymus, establishing that Tid1 promotes thymocyte survival through regulation of Bcl-2 expression. T cell-specific conditional KO mice, flow cytometry, TUNEL assay, Bcl-2 transgenic rescue Journal of immunology High 15879105
2008 Tid1 binds to the cytoplasmic domain of MuSK (identified by yeast two-hybrid), co-localizes with AChRs at motor endplates, and is required for agrin-induced AChR clustering. Tid1 knockdown disperses synaptic AChR clusters, impairs neuromuscular transmission, inhibits agrin-induced Rac and Rho GTPase activation, and reduces AChR tyrosine phosphorylation without affecting MuSK activation. Overexpression of the N-terminal half of Tid1 induces agrin/MuSK-independent AChR phosphorylation and clustering. Yeast two-hybrid, shRNA knockdown in skeletal muscle fibers, AChR clustering assays, electrophysiology, Rac/Rho activation assays, phosphorylation assays, overexpression Neuron High 19038220
2009 Tid1 forms a complex with p53 under hypoxic conditions and directs p53 translocation to the mitochondria, initiating the transcription-independent mitochondrial apoptosis pathway. Tid1 loss abrogates mitochondrial p53 translocation and inhibits apoptosis; Tid1 overexpression promotes p53 mitochondrial localization and apoptosis. Both the mitochondrial signal sequence and DnaJ domain of Tid1 are required for p53-Tid1 complex translocation from cytosol to mitochondria. Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, overexpression with domain deletion mutants, apoptosis assays Oncogene High 19935715
2010 Tid1 directly interacts with p53 (confirmed by far-western analysis). The DnaJ domain of Tid1 is necessary for this interaction, while either the N- or C-terminal domains of p53 are sufficient. shRNA depletion of Tid1 in breast cancer cells prevents p53 accumulation at mitochondria and confers resistance to apoptosis under hypoxic or genotoxic stress. Far-western blotting, domain deletion mutant constructs, shRNA knockdown, subcellular fractionation, apoptosis assays Oncotarget Medium 21311096
2011 Human mortalin (mtHsp70) together with either Tid1-L or Tid1-S co-chaperones can mediate in vitro ATP-dependent reactivation of heat-denatured protein aggregates (disaggregation activity), with the assistance of the nucleotide exchange factor Mge1. In vitro reconstitution of disaggregation activity using purified mortalin, Tid1-L, Tid1-S, and Mge1; enzyme activity assays with model substrates Cell stress & chaperones High 21811887
2011 hTid-1(S) binds to unphosphorylated c-Met receptor (MetR) and dissociates upon HGF stimulation. Overexpression of hTid-1(S) enhances MetR kinase activity and HGF-mediated cell migration. Knockdown of hTid-1 impairs both onset and amplitude of MetR phosphorylation in response to HGF without altering receptor protein levels, and inhibits ERK/MAPK and STAT3 pathways. Co-immunoprecipitation, overexpression, siRNA knockdown, kinase phosphorylation assays, migration assays, Western blotting Oncogene Medium 21242965
2012 Altered levels of DnaJA3/Tid1 (either overexpression or suppression) induce mitochondrial fragmentation in HeLa cells. The DnaJ domain (amino acids 88–168) is sufficient for fragmentation induction. An H121Q point mutation in the DnaJ domain that abolishes mtHsp70 ATPase interaction eliminates fragmentation. DnaJA3-induced fragmentation is dependent on the fission factor Drp1, and is specific to DnaJA3 (not seen with other DnaJA family members or HSC20). Overexpression, siRNA knockdown, domain deletion and point mutant constructs, live-cell imaging of mitochondrial morphology, Drp1 KO rescue The international journal of biochemistry & cell biology High 22595283
2013 Tid1-L (but not Tid1-S) interacts with EGFR/HSP70/HSP90 through its DnaJ domain, counteracts HSP90's stabilizing function on EGFR, causing EGFR ubiquitination and proteasomal degradation, thereby attenuating EGFR signaling and inhibiting lung cancer cell proliferation. Co-immunoprecipitation, overexpression, siRNA knockdown, DnaJ domain mutants, ubiquitination assays, in vivo xenograft models Cancer research High 23698466
2014 TID1 silencing leads to focal increases in mitochondrial membrane potential (Δψ) heterogeneity and ultimately loss of mtDNA and inhibition of oxygen consumption. The J-domain of TID1 is required to rescue Δψ homogeneity. Complex I aggregation underlies the focal Δψ accumulation in TID1-silenced cells. Low-dose oligomycin (ATP synthase inhibitor) phenocopies TID1 loss, indicating a connection between TID1, mitochondrial bioenergetics, and complex I stability. RNAi knockdown, mitochondrial membrane potential assays, mtDNA quantification, oxygen consumption assays, blue-native gel electrophoresis for complex I, J-domain mutant rescue Molecular and cellular biology High 24492964
2015 Tid1 is an essential mediator of canonical macroautophagy. Ectopic expression of Tid1 induces autophagy (LC3+ autophagosome foci), while Tid1 silencing drastically impairs autophagy induced by nutrient deprivation or rapamycin. Tid1 increases autophagy flux by interacting with the Beclin1-PI3K class III protein complex and connects IκB kinases to the Beclin1-containing autophagy complex. Overexpression, siRNA knockdown, co-immunoprecipitation with Beclin1 complex, autophagy flux assays, LC3 puncta imaging The Journal of biological chemistry Medium 26055714
2006 Chicken/mammalian Tid1 binds to Smad7 (and other Smad family members) through the Smad MH2 domain. Co-expression of Tid1 blocks the dorsalizing and BMP-dependent regulatory activity of Smad7 in developing Xenopus embryos, indicating functional interaction in vivo. Yeast two-hybrid, co-immunoprecipitation, Xenopus embryo overexpression/co-expression functional assay The Biochemical journal Medium 16156721
2017 Tid1-S governs the mitochondrial localization of EGFR through the mtHSP70 transportation pathway. The DnaJ domain of Tid1-S is essential for Tid1-S-mediated EGFR transport into mitochondria. Mitochondrial EGFR promotes NSCLC cell migration and invasion. Overexpression of Tid1-S and DnaJ domain mutants, subcellular fractionation, co-immunoprecipitation, migration/invasion assays Oncogenesis Medium 28714950
2018 Tid1 interacts with Galectin-7 (identified by affinity chromatography/mass spectrometry) via N-linked glycosylation of Galectin-7, and promotes ubiquitination and proteasomal degradation of Galectin-7. Tid1 also abolishes nuclear translocation of Galectin-7. Keratinocyte-specific Tid1-deficient mice show increased Galectin-7 levels, and Galectin-7 promotes metastasis through TCF3-MMP9 axis. Affinity chromatography, mass spectrometry, co-immunoprecipitation, ubiquitination assays, subcellular localization imaging, tissue-specific KO mouse model Theranostics Medium 30083263
2018 Tid1 overexpression enhances CHIP expression and induces CHIP-mediated ubiquitination and degradation of Gαs. The Tid1-CHIP complex plays an essential role in inhibiting ISO-induced cardiomyoblast hypertrophy and apoptosis, with Gαs identified as a novel substrate of CHIP. Co-immunoprecipitation, Western blotting, overexpression, ubiquitination assays, hypertrophy and apoptosis assays in H9c2 cells International journal of medical sciences Low 30443176
2019 DNAJA3 interacts with FMDV capsid protein VP1 (J domain, aa 1–168, mediates interaction; K208 of VP1 is critical). DNAJA3 induces lysosomal degradation of VP1 through interaction with LC3 to enhance the lysosomal pathway. DNAJA3 also attenuates VP1-mediated suppression of IFN-β signaling (VP1 inhibits IRF3 phosphorylation, dimerization, and nuclear translocation). DNAJA3 knockout enhances VP1-mediated IRF3 suppression. Yeast two-hybrid, co-immunoprecipitation, colocalization, domain mapping, K208A mutant virus, DNAJA3 KO cells, LC3 interaction assay, IFN-β reporter, IRF3 phosphorylation/dimerization/nuclear translocation assays Journal of virology High 30996089
2019 HSPA1A and HSPA8 are the HSP70 family proteins that physically interact with DNAJA3. DNAJA3/HSP70 complex regulates canonical NF-κB signaling during immune responses: HSP70 inhibition destabilizes the IKKβ/IκBα/NF-κB p65 complex and dampens NF-κB p65 phosphorylation in response to flagellin. This regulatory function is evolutionarily conserved (Drosophila Hsc70-4/Droj2 similarly required for immune signaling). Co-immunoprecipitation, HSP70 inhibitor treatment, siRNA knockdown, NF-κB phosphorylation assays, Drosophila genetic knockdown with infection assays Biochemical and biophysical research communications Medium 31005254
2019 A human homozygous variant p.(Arg151Thr) in TID1 (associated with developmental delay and polyneuropathy) imports efficiently into mitochondria but at a reduced rate compared to wild type. The disaggregation/chaperone activity of the mortalin/Tid1 team is compromised in the R151T variant, functioning at a level similar to the non-functional H→Q HPD-domain variant. In vitro mitochondrial import assay, in vitro protein disaggregation/chaperone activity assay, comparison to HPD domain mutant European journal of human genetics High 30770860
2021 In ClpP-null mouse cells, DNAJA3 accumulates and migrates aberrantly in blue-native gels (mitochondrial unfolded protein response). Its mitochondrial dysregulation increases DNAJA3 abundance in the nucleus. STAT1 (a putative DNAJA3 interactor) is similarly upregulated, and innate immune/interferon-stimulated gene expression (RLR sensors, nucleic acid sensors) is elevated, linking DNAJA3 nuclear redistribution to innate immune activation. Mass spectrometry, subcellular fractionation, blue-native PAGE, immunoblot, RT-PCR in ClpP-null mouse brain and fibroblasts Neurogenetics Low 34345994
2022 Solution NMR spectroscopy of human Tid1 J-domain (JD) and GF-motif reveals that Tid1-JD adopts a conformation consistent with DNAJB1 (not DNAJA1/2), and stably interacts with its subsequent GF-motif. This structural resemblance to DNAJB subfamily suggests allosteric regulation of mortalin (mtHsp70) by Tid1 similar to DNAJB members. Nuclear magnetic resonance (NMR) spectroscopy, sequence analysis BMB reports Medium 35651334

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Characterization of the roles of the Saccharomyces cerevisiae RAD54 gene and a homologue of RAD54, RDH54/TID1, in mitosis and meiosis. Genetics 171 9409820
2000 Tid1/Rdh54 promotes colocalization of rad51 and dmc1 during meiotic recombination. Proceedings of the National Academy of Sciences of the United States of America 168 11005857
1999 TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions. Proceedings of the National Academy of Sciences of the United States of America 128 10411904
2000 Promotion of Rad51-dependent D-loop formation by yeast recombination factor Rdh54/Tid1. Genes & development 119 10970884
1999 Sister chromatid-based DNA repair is mediated by RAD54, not by DMC1 or TID1. The EMBO journal 97 10228176
1998 A novel human DnaJ protein, hTid-1, a homolog of the Drosophila tumor suppressor protein Tid56, can interact with the human papillomavirus type 16 E7 oncoprotein. Virology 87 9683573
2009 Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer. Oncogene 77 19935715
2003 Crossover interference in Saccharomyces cerevisiae requires a TID1/RDH54- and DMC1-dependent pathway. Genetics 69 12702674
2001 Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70. Current biology : CB 69 11719219
2006 Tid1 isoforms are mitochondrial DnaJ-like chaperones with unique carboxyl termini that determine cytosolic fate. The Journal of biological chemistry 62 16531398
2006 Tid1/Rdh54 promotes dissociation of Dmc1 from nonrecombinogenic sites on meiotic chromatin. Genes & development 62 16980587
2010 Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis. Oncotarget 58 21311096
2012 Saccharomyces cerevisiae Dmc1 and Rad51 proteins preferentially function with Tid1 and Rad54 proteins, respectively, to promote DNA strand invasion during genetic recombination. The Journal of biological chemistry 54 22761450
2008 A mammalian homolog of Drosophila tumorous imaginal discs, Tid1, mediates agrin signaling at the neuromuscular junction. Neuron 53 19038220
2004 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. Molecular and cellular biology 51 14993262
2001 hTid-1, a human DnaJ protein, modulates the interferon signaling pathway. The Journal of biological chemistry 51 11679576
2009 Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma. The Journal of pathology 49 19681071
2004 Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells. Cancer research 49 15520177
2007 Single molecule imaging of Tid1/Rdh54, a Rad54 homolog that translocates on duplex DNA and can disrupt joint molecules. The Journal of biological chemistry 48 17704061
2002 Human Rad54B is a double-stranded DNA-dependent ATPase and has biochemical properties different from its structural homolog in yeast, Tid1/Rdh54. Nucleic acids research 47 11884632
2019 Cellular DNAJA3, a Novel VP1-Interacting Protein, Inhibits Foot-and-Mouth Disease Virus Replication by Inducing Lysosomal Degradation of VP1 and Attenuating Its Antagonistic Role in the Beta Interferon Signaling Pathway. Journal of virology 46 30996089
2003 Schizosaccharomyces pombe Rdh54 (TID1) acts with Rhp54 (RAD54) to repair meiotic double-strand breaks. Molecular biology of the cell 46 14551247
2013 Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR Ubiquitinylation and degradation. Cancer research 42 23698466
2002 HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of Ikappa B kinase beta subunit. The Journal of biological chemistry 40 11927590
2011 Reactivation of protein aggregates by mortalin and Tid1--the human mitochondrial Hsp70 chaperone system. Cell stress & chaperones 39 21811887
2005 Tid1 negatively regulates the migratory potential of cancer cells by inhibiting the production of interleukin-8. Cancer research 39 16204048
2005 Tid-1 interacts with the von Hippel-Lindau protein and modulates angiogenesis by destabilization of HIF-1alpha. Cancer research 38 15805242
2014 Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity. Molecular and cellular biology 37 24492964
2005 Molecular mechanism of hTid-1, the human homolog of Drosophila tumor suppressor l(2)Tid, in the regulation of NF-kappaB activity and suppression of tumor growth. Molecular and cellular biology 37 15601829
2018 HSP40 co-chaperone protein Tid1 suppresses metastasis of head and neck cancer by inhibiting Galectin-7-TCF3-MMP9 axis signaling. Theranostics 35 30083263
2002 The human DnaJ protein, hTid-1, enhances binding of a multimer of the herpes simplex virus type 1 UL9 protein to oris, an origin of viral DNA replication. Proceedings of the National Academy of Sciences of the United States of America 34 11854491
2012 Mitochondrial chaperone DnaJA3 induces Drp1-dependent mitochondrial fragmentation. The international journal of biochemistry & cell biology 30 22595283
2005 Human tumorous imaginal disc 1 (TID1) associates with Trk receptor tyrosine kinases and regulates neurite outgrowth in nnr5-TrkA cells. The Journal of biological chemistry 28 15753086
2008 Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor. International journal of molecular medicine 26 18097612
2004 Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli. Oncogene 26 15156195
2004 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. Molecular and cellular biology 26 15572682
2001 Genomic organization and expression of the human tumorous imaginal disc (TID1) gene. Gene 26 11707338
2003 TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells. Oncogene 25 12879007
2020 DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells. Cancers 23 33233689
2017 Tid1-S regulates the mitochondrial localization of EGFR in non-small cell lung carcinoma. Oncogenesis 23 28714950
2004 Identification of a hTid-1 mutation which sensitizes gliomas to apoptosis. FEBS letters 23 15589840
2019 HSP70/DNAJA3 chaperone/cochaperone regulates NF-κB activity in immune responses. Biochemical and biophysical research communications 22 31005254
2020 Rdh54/Tid1 inhibits Rad51-Rad54-mediated D-loop formation and limits D-loop length. eLife 21 33185188
2007 Expression of EIF3-p48/INT6, TID1 and Patched in cancer, a profiling of multiple tumor types and correlation of expression. Journal of biomedical science 19 17385060
2016 Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer. Oncotarget 17 26919236
2009 The mitochondrial protein hTID-1 partners with the caspase-cleaved adenomatous polyposis cell tumor suppressor to facilitate apoptosis. Gastroenterology 17 19900451
2021 Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse. Neurogenetics 16 34345994
2016 Mitochondrial co-chaperone protein Tid1 is required for energy homeostasis during skeletal myogenesis. Stem cell research & therapy 16 27927223
2015 Tid1, the Mammalian Homologue of Drosophila Tumor Suppressor Tid56, Mediates Macroautophagy by Interacting with Beclin1-containing Autophagy Protein Complex. The Journal of biological chemistry 15 26055714
2008 New dogs in the dogma: Lrp4 and Tid1 in neuromuscular synapse formation. Neuron 15 19038209
2018 Tumorous imaginal disc 1 (TID1) inhibits isoproterenol-induced cardiac hypertrophy and apoptosis by regulating c-terminus of hsc70-interacting protein (CHIP) mediated degradation of Gαs. International journal of medical sciences 14 30443176
2011 hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas. Oncogene 14 21242965
2007 Htid-1, the human homolog of the Drosophila melanogaster l(2)tid tumor suppressor, defines a novel physiological role of APC. Cellular signalling 14 17588722
2011 Identification of bilateral changes in TID1 expression in the 6-OHDA rat model of Parkinson's disease. PloS one 12 22016808
2005 Tid1 is required for T cell transition from double-negative 3 to double-positive stages. Journal of immunology (Baltimore, Md. : 1950) 12 15879105
2022 Putting human Tid-1 in context: an insight into its role in the cell and in different disease states. Cell communication and signaling : CCS 11 35854300
2015 The Role of the Phylogenetically Conserved Cochaperone Protein Droj2/DNAJA3 in NF-κB Signaling. The Journal of biological chemistry 11 26245905
2013 Tid1/Rdh54 translocase is phosphorylated through a Mec1- and Rad53-dependent manner in the presence of DSB lesions in budding yeast. DNA repair 11 23473644
2023 DNAJA3 regulates B cell development and immune function. Biomedical journal 10 37487907
2019 A novel variant of the human mitochondrial DnaJ protein, Tid1, associates with a human disease exhibiting developmental delay and polyneuropathy. European journal of human genetics : EJHG 10 30770860
2019 Tid1-S attenuates LPS-induced cardiac hypertrophy and apoptosis through ER-a mediated modulation of p-PI3K/p-Akt signaling cascade. Journal of cellular biochemistry 10 31081962
2020 Ganoderma microsporum immunomodulatory protein, GMI, promotes C2C12 myoblast differentiation in vitro via upregulation of Tid1 and STAT3 acetylation. PloS one 8 33382817
2022 DNAJA3 Interacts with PEDV S1 Protein and Inhibits Virus Replication by Affecting Virus Adsorption to Host Cells. Viruses 7 36366511
2006 Tid1 is a Smad-binding protein that can modulate Smad7 activity in developing embryos. The Biochemical journal 7 16156721
2023 A genetic basis of mitochondrial DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma. Hepatology (Baltimore, Md.) 5 37870291
2021 Loss of Tid1/DNAJA3 Co-Chaperone Promotes Progression and Recurrence of Hepatocellular Carcinoma after Surgical Resection: A Novel Model to Stratify Risk of Recurrence. Cancers 5 33406664
2018 Purification of Saccharomyces cerevisiae Homologous Recombination Proteins Dmc1 and Rdh54/Tid1 and a Fluorescent D-Loop Assay. Methods in enzymology 5 29458764
2025 DNAJA3 interacts with ASFV MGF360-14L protein and reduces MGF360-14L antagonistic role on Beta interferon production. International journal of biological macromolecules 4 40233912
2024 Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism. Journal of cachexia, sarcopenia and muscle 4 39132696
2022 Structural resemblance of the DNAJA-family protein, Tid1, to the DNAJB-family Hsp40. BMB reports 4 35651334
2020 Optimization of expression and purification of mitochondrial HSP 40 (Tid1-L) chaperone: Role of mortalin and tid1 in the reactivation and amyloid inhibition of proteins. Saudi journal of biological sciences 3 33100870

Missed literature

Know a paper Affinage missed for DNAJA3? Flag it for the maintainers and the community.

No submissions yet.