Affinage

DNAJA2

DnaJ homolog subfamily A member 2 · UniProt O60884

Length
412 aa
Mass
45.7 kDa
Annotated
2026-06-09
16 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAJA2 is a class A J-domain co-chaperone that partners with Hsc70/Hsp70 to govern the fate of client proteins, switching the chaperone system between folding, holding, and degradation depending on the substrate and context (PMID:23091061, PMID:39012012). Mechanistically, it binds substrate and then releases it during ATP-dependent transfer to Hsc70, a step that requires both its J domain and the region between its zinc-finger motifs (PMID:23091061), and phosphorylation of specific J-domain residues (Y10, S51) tunes the holding-to-folding balance of the Hsc70 system (PMID:39012012). Beyond promoting folding, DNAJA2 can route the Hsc70 system toward degradation, tipping clients such as CFTR toward Hsc70/Hsp70-CHIP-mediated ER-associated degradation (PMID:31408507) and directing HSC70 toward LAMP2A-dependent chaperone-mediated autophagy to clear specific clients, including the centriolar satellite proteins PCM1 and CEP290 to preserve centrosome homeostasis and genome stability (PMID:37640708) and sumoylated CSB during transcription-coupled nucleotide excision repair (PMID:37907457). It also stabilizes the broad cytosolic proteome and selectively buffers missense-mutant proteins against proteasomal turnover, and maintains extended, aggregation-resistant conformations of the TDP-43 prion-like low-complexity domain (PMID:39117455, PMID:39618332). DNAJA2 additionally performs receptor-proximal functions, binding the insulin receptor to block AP2-mediated endocytosis and sustain insulin signaling and hepatic glycogen storage, with its loss causing neonatal lethality in knockout mice (PMID:41233317), and interacting with trimeric G proteins to modulate beta-adrenergic cAMP/CREB signaling (PMID:18595009).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2008 Medium

    Established that DNAJA2 acts beyond generic protein folding by engaging receptor signaling machinery, directly binding trimeric G proteins and modulating beta-adrenergic output.

    Evidence Co-immunoprecipitation with G proteins plus cAMP and CREB phosphorylation readouts in HEK293 and CAD cells

    PMID:18595009

    Open questions at the time
    • Does not define which J-domain/Hsc70 activity mediates the signaling effect
    • Single lab, no in vivo confirmation
    • Mechanism of G protein complex assembly unresolved
  2. 2012 High

    Defined the core biochemical mechanism by which DNAJA2 delivers clients to Hsc70, showing substrate release is an active, ATP- and J-domain-dependent step distinct from substrate binding.

    Evidence Purified-protein folding and HERG trafficking assays with domain-deletion mutants (DJA2-Δm2) and limited proteolysis

    PMID:23091061

    Open questions at the time
    • Did not establish in vivo client repertoire
    • Structural basis of the inter-zinc-finger release region not resolved
    • Physiological consequences of release defects untested
  3. 2019 Medium

    Showed DNAJA2 can bias the Hsc70 system toward client degradation rather than folding, defining a degradative branch via the CHIP E3 ligase.

    Evidence Overexpression/knockdown CFTR degradation assays with DNAJA1 comparison and CHIP-dependence tests in cells

    PMID:31408507

    Open questions at the time
    • No direct demonstration of DNAJA2-CHIP physical complex
    • Generality across other clients untested
    • Single lab
  4. 2023 High

    Connected DNAJA2 to chaperone-mediated autophagy, demonstrating it routes HSC70 to LAMP2A to degrade specific clients in two distinct contexts: centrosome homeostasis (PCM1/CEP290) and DNA repair (sumoylated CSB).

    Evidence Knockout/knockdown cells, reciprocal Co-IP, LAMP2A-dependent lysosomal degradation, mitosis/micronuclei and cGAS-STING phenotyping, and TC-NER functional assays

    PMID:37640708 PMID:37907457

    Open questions at the time
    • How DNAJA2 selects CMA versus folding fate for a client is undefined
    • Recognition of the sumoylation/substrate signal not biochemically reconstituted
    • Relative contribution of CMA versus other degradation routes unquantified
  5. 2024 Medium

    Resolved how DNAJA2 activity is tuned and broadened its client conformational role, linking J-domain phosphorylation to the holding/folding balance and showing it maintains aggregation-resistant TDP-43 conformations.

    Evidence Phosphomimetic and phosphorylated J-domain variants with biochemical/structural analysis; single-molecule FRET and bulk aggregation assays on the TDP-43 LCD

    PMID:39012012 PMID:39117455

    Open questions at the time
    • Kinases responsible for Y10/S51 phosphorylation not identified
    • In vivo relevance of phospho-tuning untested
    • TDP-43 work limited to LCD in vitro, single lab
  6. 2025 Medium

    Expanded DNAJA2's physiological scope to proteostatic buffering, metabolic regulation, and antiviral defense, including a non-chaperone receptor-trafficking role at the insulin receptor essential for survival.

    Evidence BioID mutation-library screen with turnover readouts; reciprocal Co-IP and DNAJA2 knockout mice with insulin signaling/glycogen phenotypes; IP-MS and Co-IP with viral V/NS3 proteins and IFN-β readouts

    PMID:37633595 PMID:39618332 PMID:41233317 PMID:41430554

    Open questions at the time
    • Whether IR binding requires canonical Hsc70/J-domain activity is unclear
    • Mechanism distinguishing pro-viral (JEV NS3 stabilization) from antiviral (NDV/MDA5-MAVS) outcomes unresolved
    • Selectivity rules for mutant-protein buffering not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DNAJA2 chooses among folding, holding, degradation (proteasomal versus CMA), and non-chaperone receptor functions for a given client remains unresolved.
  • No unifying model for fate selection
  • Upstream signals controlling phospho-tuning in vivo unknown
  • Full physiological client repertoire uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1 R-HSA-73894 DNA Repair 1
Partners
CEP290ERCC6HSPA8INSRLAMP2APCM1STUB1TARDBP

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 DNAJA2 (DJA2) possesses a substrate release mechanism essential for chaperone-mediated folding: a mutant lacking the region between the zinc finger motifs (DJA2-Δm2) can bind substrate but cannot release it during transfer to Hsc70. Substrate release requires the J domain and ATP hydrolysis by Hsc70, and the nucleotide dependence of release differs between DJA2 and DJA1. Purified protein assays, domain deletion/mutation analysis, luciferase folding assay, HERG trafficking assay, limited proteolysis The Journal of biological chemistry High 23091061
2019 DNAJA2 overexpression (but not DNAJA1 overexpression) promotes CFTR degradation at the endoplasmic reticulum via the Hsc70/Hsp70-CHIP E3 ubiquitin ligase axis, demonstrating that DNAJA2 can tip the Hsc70 chaperone system toward client degradation rather than folding. Overexpression and knockdown in cell-based CFTR trafficking/degradation assays, co-chaperone comparisons, CHIP involvement assessed by modulation experiments PloS one Medium 31408507
2023 DNAJA2 maintains centrosome homeostasis by facilitating HSC70-mediated chaperone-mediated autophagy (CMA) to degrade centriolar satellite proteins PCM1 and CEP290 via the lysosome receptor LAMP2A. Loss of DNAJA2 or LAMP2A elevates PCM1/CEP290 levels, causing aberrant mitosis, chromosome missegregation, micronuclei formation, and cGAS-STING pathway activation. DNAJA2 knockout/knockdown cells, co-immunoprecipitation, LAMP2A-dependent lysosomal degradation assays, mitosis phenotyping, cGAS-STING reporter assays Nature communications High 37640708
2008 DNAJA2 (RDJ2) directly interacts with receptor-coupled trimeric G proteins and modulates beta-adrenergic signaling: its expression in HEK293 and CAD cells increased isoproterenol-stimulated cAMP levels and CREB phosphorylation. The composition of the DNAJA2-chaperone complex is distinct from that of CSPα. Co-immunoprecipitation (direct interaction with G proteins), transient transfection, cAMP measurement, CREB phosphorylation assay Cell stress & chaperones Medium 18595009
2023 DNAJA2 facilitates HSC70-mediated chaperone-mediated autophagy (CMA) degradation of sumoylated CSB (Cockayne syndrome group B protein) during transcription-coupled nucleotide excision repair (TC-NER). DNAJA2 interacts with CSB and enables HSC70 recognition of sumoylated CSB, triggering removal of both CSB and RNA Pol II from DNA lesion sites via LAMP2A-dependent lysosomal pathway; loss of DNAJA2 abolishes CSB degradation and blocks TC-NER. Co-immunoprecipitation, DNAJA2 knockdown/knockout, LAMP2A-dependent lysosomal degradation assays, TC-NER functional assays, sumoylation analysis Cell discovery High 37907457
2024 DNAJA2 stabilizes extended (unfolded) conformational states of the prion-like low-complexity domain (LCD) of TDP-43, suppressing its aggregation. Single-molecule FRET showed DNAJA2 counteracts the collapsed conformations promoted by the ALS-associated A315T mutation, linking chaperone-mediated conformational extension to bulk aggregation suppression. Single-molecule FRET (smFRET), bulk aggregation assays, comparison with Hero11 protein RNA (New York, N.Y.) Medium 39117455
2024 Phosphorylation of specific J-domain residues of DNAJA2 regulates the holding/folding balance of the Hsc70 system. Pseudophosphorylation of Y10 causes partial disordering of the J domain (reducing cochaperone collaboration with Hsc70), while S51E weakens DNAJA2-Hsc70 interactions without large structural reorganization. Both enhance the holding-to-folding ratio. S51 phosphorylation appears class A JDP-specific. Biochemical assays, structural analysis (NMR/biochemical), pseudophosphorylation mutagenesis, phosphomimetic and truly-phosphorylated variant comparison Protein science : a publication of the Protein Society Medium 39012012
2025 DNAJA2 acts as a buffer against proteasomal degradation of cytosolic proteins carrying missense mutations: BioID proximity labeling identified DNAJA2 as a key interactor with misfolded mutant proteins, and DNAJA2 absence increases turnover of mutant but not wild-type protein. DNAJA2 exhibits two behaviors: stabilizing a broad set of cytosolic proteins (including wild-type) and specifically buffering certain mutant proteins. BioID proximity labeling, human mutation library screen, knockdown/knockout with proteasomal degradation readouts Journal of cell science Medium 39618332
2025 DNAJA2 binds directly to the insulin receptor (IR) and prevents adaptor protein 2 (AP2)-mediated spontaneous IR endocytosis by inhibiting the IR-AP2 interaction. Loss of DNAJA2 reduces IR plasma membrane localization, suppresses insulin-stimulated signaling, and inhibits glycogen synthesis/storage in the liver during embryogenesis, causing neonatal lethality in DNAJA2-knockout mice. Co-immunoprecipitation (DNAJA2-IR and IR-AP2 interactions), DNAJA2 knockout mice, plasma membrane IR localization assay, insulin signaling cascade readouts, glycogen synthesis/storage assays Nature communications High 41233317
2025 DNAJA2 interacts with the Newcastle disease virus (NDV) V protein (interaction domain mapped to residues 101–367 of DNAJA2) and inhibits NDV replication by upregulating MDA5 and MAVS expression to enhance IFN-β and interferon-stimulated gene production. DNAJA2 knockdown promotes viral replication. IP-MS, co-immunoprecipitation, confocal colocalization, overexpression/knockdown with viral replication and IFN-β readouts BMC microbiology Medium 41430554
2023 DNAJA2 interacts with JEV NS3 protein (via its C-terminal domain) and also with NS5, colocalizing with viral dsRNA. DNAJA2 overexpression increases JEV infection and NS3 protein levels, while knockdown causes NS3 degradation that is rescued by the proteasome inhibitor MG132, indicating DNAJA2 protects NS3 from proteasomal degradation to promote JEV infection. Co-IP-MS, co-immunoprecipitation, C-terminal domain mapping, overexpression/knockdown with viral infection and protein stability readouts, MG132 rescue experiment Virus research Medium 37633595

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The DNAJA2 substrate release mechanism is essential for chaperone-mediated folding. The Journal of biological chemistry 41 23091061
2019 Hsp70 and DNAJA2 limit CFTR levels through degradation. PloS one 25 31408507
2023 DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability. Nature communications 23 37640708
2008 RDJ2 (DNAJA2) chaperones neural G protein signaling pathways. Cell stress & chaperones 17 18595009
1999 R73A and H144Q mutants of the yeast mitochondrial cyclophilin Cpr3 exhibit a low prolyl isomerase activity in both peptide and protein-folding assays. FEBS letters 17 10025965
2018 The yeast mitochondrial permeability transition is regulated by reactive oxygen species, endogenous Ca2+ and Cpr3, mediating cell death. Biochimica et biophysica acta. Bioenergetics 15 30031690
2022 Histone acetyltransferase HAM1 interacts with molecular chaperone DNAJA2 and confers immune responses through salicylic acid biosynthetic genes in cassava. Plant, cell & environment 10 36451539
2023 Heat shock protein DNAJA2 regulates transcription-coupled repair by triggering CSB degradation via chaperone-mediated autophagy. Cell discovery 8 37907457
2024 DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43. RNA (New York, N.Y.) 6 39117455
2024 Pseudophosphorylation of single residues of the J-domain of DNAJA2 regulates the holding/folding balance of the Hsc70 system. Protein science : a publication of the Protein Society 4 39012012
2023 DnaJA2 interacts with Japanese encephalitis virus NS3 via its C-terminal to promote viral infection. Virus research 4 37633595
2017 Unfolding of CPR3 Gets Initiated at the Active Site and Proceeds via Two Intermediates. Biophysical journal 4 28256221
2025 The co-chaperone DNAJA2 buffers proteasomal degradation of cytosolic proteins with missense mutations. Journal of cell science 2 39618332
2016 NMR assignments of mitochondrial cyclophilin Cpr3 from Saccharomyces cerevisiae. Biomolecular NMR assignments 1 26897529
2025 Heat shock protein DNAJA2 controls insulin signaling and glucose homeostasis by preventing spontaneous insulin receptor endocytosis. Nature communications 0 41233317
2025 DNAJA2 inhibits Newcastle disease virus replication by targeting its V protein to modulate the MDA5-MAVS pathway. BMC microbiology 0 41430554

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