DNAJB4 (HLJ1, "human liver DnaJ-like protein"; also DNAJW) is a cytosolic HSP40/J-domain co-chaperone of the DNAJB subfamily and a paralog of DNAJB1. Through its N-terminal J domain it stimulates the ATPase activity of HSP70 (HSPA1A/HSPA1B), binding misfolded client proteins and delivering them to HSP70 to drive their folding, refolding and disaggregation. It is a homodimer, is heat-inducible, and is broadly expressed with high levels in striated muscle, where it localizes to the sarcomeric Z-disc and contributes to myofibril/Z-disc proteostasis. Biallelic loss-of-function variants in DNAJB4 cause an autosomal recessive congenital myopathy with early respiratory failure (CMYO21), reflecting its role as a muscle chaperone. It also interacts with the mu-opioid receptor (OPRM1) C-terminal tail and with aggregation-prone clients such as huntingtin and ataxin-1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006457 protein folding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) annotation that DNAJB4 participates in protein folding. As an HSP70 co-chaperone DNAJB4 assists folding rather than catalyzing it autonomously; folding is a downstream process outcome of its co-chaperone activity. Reason: DNAJB4 is a J-protein co-chaperone that stimulates the HSP70 folding machine; protein folding is a real biological-process outcome but the gene's direct molecular role is HSP70 ATPase stimulation and client binding, so folding is non-core. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B |
| GO:0051087 protein-folding chaperone binding | IBA GO_REF:0000033 | ACCEPT | Summary: DNAJB4 binds the HSP70 chaperone (HSPA1A/HSPA1B) to deliver clients and stimulate ATP hydrolysis. Binding the folding chaperone is central to its co-chaperone role and is corroborated by IPI evidence against HSP70 isoforms. Reason: Direct binding to HSP70 is the structural basis of DNAJB4 co-chaperone activity and is supported both phylogenetically and by experimental IPI annotations to HSPA1A/HSPA1B. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: DNAJB4 is a cytosolic J-protein; cytosolic localization/site of action is supported by phylogeny and by direct experimental evidence (HPA IDA; PubMed:21231916; PubMed:18837411). Reason: The cytosol is where DNAJB4 acts as an HSP70 co-chaperone; the IBA call agrees with multiple experimental cytosol annotations. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic transfer (from PANTHER node including yeast Sis1/DnaJ family) assigning a transcriptional repression role. There is no direct experimental evidence that DNAJB4 regulates RNA polymerase II transcription in humans; this is most consistent with over-annotation from a divergent family branch. Reason: No experimental support for a Pol II transcription-regulation role for DNAJB4; the term derives from IBA transfer across the broad DnaJ family and conflicts with DNAJB4's documented cytosolic co-chaperone function. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated localization to cytoplasm, consistent with the experimentally supported cytosolic site of action. Reason: Correct compartment for this cytosolic co-chaperone; IEA agrees with stronger experimental and IBA cytosol/cytoplasm evidence. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Automated plasma-membrane localization derived from the UniProt cell-membrane annotation, which itself reflects an indirect association via the mu-opioid receptor (OPRM1) C-tail interaction rather than DNAJB4 being an intrinsic membrane protein. Reason: Membrane association is indirect (client-mediated, via OPRM1) and context-specific; retained as non-core because DNAJB4 is a soluble cytosolic chaperone, not a membrane component. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt The C-terminal section interacts with the C-terminal tail of OPRM1 |
| GO:0006457 protein folding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic annotation of protein folding, redundant with the IBA protein folding call and consistent with the J-protein co-chaperone role. Reason: Same downstream process rationale as the IBA protein folding annotation; DNAJB4 assists rather than autonomously catalyzes folding. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B |
| GO:0006986 response to unfolded protein | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: DNAJB4 is heat-inducible and binds/handles unfolded and aggregation-prone clients as part of the stress response; participation in the response to unfolded protein is well supported. Reason: Consistent with DNAJB4's heat-shock induction and client-handling role; a genuine process annotation but downstream of its molecular co-chaperone function. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt INDUCTION: By heat shock |
| GO:0030018 Z disc | IEA GO_REF:0000044 | ACCEPT | Summary: Automated Z-disc localization, redundant with and corroborated by the experimental IDA Z-disc annotation (PubMed:36264506). Reason: Z-disc localization is experimentally established and central to DNAJB4's muscle proteostasis role; the IEA call is correct. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Cytoplasm, myofibril, sarcomere, Z line |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000117 | ACCEPT | Summary: Rule-based electronic annotation of chaperone binding, redundant with the IBA and IPI protein-folding chaperone binding annotations (binding to HSP70). Reason: Correct molecular function; DNAJB4 binds HSP70, supported by stronger IPI/IBA evidence. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: High-throughput interaction capturing DNAJB4-RUVBL2 (Q9Y230). The bare protein binding term is uninformative and records a single interactome partner not central to the co-chaperone function. Reason: Records a real interaction but bare protein binding is uninformative per curation guidelines; the RUVBL2 partner does not define DNAJB4's core chaperone function. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Q9UDY4; Q9Y230: RUVBL2 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegeneration interactome screen capturing DNAJB4 interactions with aggregation-prone clients huntingtin (HTT, P42858) and ataxin-1 (ATXN1, P54253). Bare protein binding is uninformative, though the partners are consistent with DNAJB4 handling aggregation-prone substrates. Reason: Real interactions with aggregation-prone clients, but bare protein binding is uninformative as a core MF; the meaningful function (client binding/HSP70 delivery) is captured elsewhere. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Q9UDY4; P42858: HTT |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence places a pool of DNAJB4 in the nucleoplasm. This is a minor/secondary localization relative to its predominant cytosolic and Z-disc sites of action. Reason: Antibody-based nucleoplasm signal is plausible but peripheral; DNAJB4's characterized function is cytosolic/sarcomeric, so this is non-core. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct (HPA immunofluorescence) evidence for cytosolic localization, the principal compartment in which DNAJB4 acts. Reason: IDA-supported cytosol localization matches the documented site of co-chaperone action. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence plasma-membrane signal, consistent with the membrane-associated pool reported via the OPRM1 interaction but secondary to the cytosolic localization. Reason: Plasma-membrane association of DNAJB4 is indirect/client-mediated and context-specific; not part of its core cytosolic chaperone function. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt The C-terminal section interacts with the C-terminal tail of OPRM1 |
| GO:0005737 cytoplasm | EXP PMID:18837411 Preparation of the anti-HLJ1 monoclonal antibodies and estab... | ACCEPT | Summary: Experimental (antibody-based) evidence for cytoplasmic localization of DNAJB4/HLJ1, consistent with its cytosolic co-chaperone role. Reason: Experimental cytoplasmic localization corroborates the cytosol annotations and the established site of action. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Cytoplasmic according to PubMed:18837411 |
| GO:0005886 plasma membrane | EXP PMID:16542645 A member of the heat shock protein 40 family, hlj1, binds to... | KEEP AS NON CORE | Summary: Membrane association reported from the study showing DNAJB4/HLJ1 binds the C-terminal tail of the mu-opioid receptor (OPRM1). This reflects an indirect, client-mediated membrane pool rather than an intrinsic membrane localization. Reason: The plasma-membrane association is a consequence of binding the membrane protein OPRM1; DNAJB4 is a soluble cytosolic chaperone, so this is a context-specific, non-core localization. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt The C-terminal section interacts with the C-terminal tail of OPRM1 |
| GO:0030018 Z disc | IDA PMID:36264506 Loss of function variants in DNAJB4 cause a myopathy with ea... | ACCEPT | Summary: Direct immunofluorescence demonstrates DNAJB4 localizes to the sarcomeric Z-disc in muscle, and it is lost from patient muscle/fibroblasts. This is a key, functionally relevant localization. Reason: Experimentally established Z-disc localization underpins DNAJB4's role in myofibril/Z-disc proteostasis and is supported by loss in CMYO21 patient tissue. Supporting Evidence: PMID:36264506 DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients |
| GO:0051087 protein-folding chaperone binding | IPI PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Functional study of the mammalian HSP70/DNAJ machine; DNAJB4 binds HSP70 isoforms (HSPA1A/HSPA1B) as a co-chaperone. Direct chaperone-binding evidence. Reason: Binding to HSP70 chaperones is the core molecular interaction of DNAJB4 as a J-protein co-chaperone. Supporting Evidence: file:human/DNAJB4/DNAJB4-goa.tsv GO:0051087 protein-folding chaperone binding molecular_function ECO:0000353 IPI PMID:21231916 UniProtKB:P0DMV8 |
| GO:0001671 ATPase activator activity | IDA PMID:24318877 Binding of human nucleotide exchange factors to heat shock p... | ACCEPT | Summary: Direct in vitro evidence that DNAJB4 (DnaJB4), as a J-protein, stimulates HSP70 ATPase activity (and luciferase refolding) when combined with HSP70 and nucleotide exchange factors. This is the core molecular function of DNAJB4. Reason: J-domain stimulation of HSP70 ATP hydrolysis is the defining molecular activity of DNAJB4 and is experimentally demonstrated. Supporting Evidence: PMID:24318877 we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the combinations in ATPase and luciferase refolding assays |
| GO:0005829 cytosol | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Direct evidence places DNAJB4 in the cytosol, consistent with all other localization data and its co-chaperone role. Reason: IDA cytosol localization corroborates the established cytosolic site of action. Supporting Evidence: file:human/DNAJB4/DNAJB4-goa.tsv GO:0005829 cytosol cellular_component ECO:0000314 IDA PMID:21231916 |
| GO:0005515 protein binding | IPI PMID:21255413 A novel neuron-enriched protein SDIM1 is down regulated in A... | KEEP AS NON CORE | Summary: Specific interaction with the neuron-enriched protein SDIM1 (Q6ZPB5), where SDIM1 attenuates cell death induced by DNAJB4 over-expression. Bare protein binding is uninformative as a core function but records a real, characterized interaction. Reason: Documented DNAJB4-SDIM1 interaction; bare protein binding is uninformative per curation guidelines and the interaction is peripheral to the core chaperone function. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt Also interacts with SDIM1 |
| GO:0006986 response to unfolded protein | TAS PMID:9546042 Isolation of a new member of DnaJ-like heat shock protein 40... | KEEP AS NON CORE | Summary: The original cloning paper describes HLJ1/DNAJB4 as a heat-inducible HSP40, supporting a role in the response to unfolded protein. Reason: Consistent with DNAJB4's stress-induced client-handling role; a genuine process annotation downstream of its molecular co-chaperone function. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt INDUCTION: By heat shock |
| GO:0009408 response to heat | TAS PMID:9546042 Isolation of a new member of DnaJ-like heat shock protein 40... | KEEP AS NON CORE | Summary: DNAJB4/HLJ1 is induced by heat shock, supporting involvement in the response to heat. Reason: Heat induction is experimentally documented; participation in the heat response is a genuine but non-core (stress-context) process annotation. Supporting Evidence: file:human/DNAJB4/DNAJB4-uniprot.txt INDUCTION: By heat shock |
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Download this section (compressed HTML)Q: What is the specific client repertoire of DNAJB4 at the muscle Z-disc, and which clients accumulate/aggregate upon DNAJB4 loss to drive CMYO21 myopathology?
Q: Is DNAJB4 functionally redundant with its paralogs DNAJB1 and DNAJB6 in muscle, and does the Z-disc role overlap with the DNAJB6 LGMD-D1 mechanism?
Experiment: Affinity purification-mass spectrometry of tagged DNAJB4 from muscle cells (with HSP70 as co-bait) to define its client interactome and compare with DNAJB6.
Experiment: Reconstituted ATPase and disaggregation/refolding assays comparing wild-type DNAJB4 with CMYO21 variants (R25Q, L262S, K286Ter) to quantify loss of HSP70-stimulating and client-handling activity.
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