Existing Annotations Review

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

Core Functions

J-domain co-chaperone that stimulates the ATPase activity of HSP70 (HSPA1A/HSPA1B), driving HSP70-mediated folding, refolding and disaggregation of client proteins.

Molecular Function:

ATPase activator activity

Cellular Locations:

cytosol

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
file:human/DNAJB4/DNAJB4-uniprot.txt
Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B

Binds the HSP70 chaperone and misfolded/aggregation-prone client proteins, recruiting clients to HSP70 for folding; in striated muscle this supports myofibril and Z-disc proteostasis.

Molecular Function:

protein-folding chaperone binding

Cellular Locations:

cytosol Z disc

Supporting Evidence:

PMID:36264506
DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients
file:human/DNAJB4/DNAJB4-uniprot.txt
Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:16542645

A member of the heat shock protein 40 family, hlj1, binds to the carboxyl tail of the human mu opioid receptor.

The C-terminal portion of DNAJB4/HLJ1 interacts with the C-terminal tail of the human mu-opioid receptor (OPRM1), conferring a membrane-associated pool.

PMID:18837411

Preparation of the anti-HLJ1 monoclonal antibodies and establishment of method for detection of the antigen.

DNAJB4/HLJ1 is detected in the cytoplasm.

PMID:21231916

The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities.

DNAJB4 is a cytosolic DNAJ/HSP40 co-chaperone of the HSP70 machine with client-dependent refolding/anti-aggregation activities.

PMID:21255413

A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor cells.

SDIM1 interacts with DNAJB4 and attenuates DNAJB4 over-expression-induced cell death in neuro-progenitor cells.

PMID:24318877

Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro.

DNAJB4, as a J-protein co-chaperone, stimulates HSP70 ATPase activity and supports luciferase refolding in combination with HSP70 and nucleotide exchange factors.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

DNAJB4 interacts with aggregation-prone neurodegeneration-associated clients including huntingtin (HTT) and ataxin-1 (ATXN1).

PMID:36264506

Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure.

Biallelic loss-of-function DNAJB4 variants cause an autosomal recessive myopathy with early respiratory failure (CMYO21).
DNAJB4 normally localizes to the Z-disc and is absent from patient muscle and fibroblasts; knockout muscle accumulates Z-disc proteins and chaperones, indicating a role in myofibril/Z-disc proteostasis.

PMID:9546042

Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from human liver.

HLJ1/DNAJB4 is a 337-residue human HSP40/DnaJ-like protein that is induced by heat shock.

Suggested Experiments

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.

📚 Additional Documentation

Notes

(DNAJB4-notes.md)

DNAJB4 (HLJ1 / DNAJW) research notes

UniProt: Q9UDY4. 337 aa. DnaJ homolog subfamily B member 4. Cytosolic HSP40/J-protein,
paralog of DNAJB1. J-domain at residues 2-70.

Core function: HSP70 co-chaperone (class B J-protein)

UniProt FUNCTION: "Probable chaperone. Stimulates ATP hydrolysis and the folding of unfolded
proteins mediated by HSPA1A/B (in vitro) (PubMed:24318877)."
PMID:36264506
PMID:36264506
GOA: GO:0001671 ATPase activator activity IDA PMID:24318877 — the experimentally supported core MF
(stimulates HSP70 ATP hydrolysis).
GOA: GO:0051087 protein-folding chaperone binding IPI to HSPA1A/HSPA1B (P0DMV8/P0DMV9, P17066) —
binds HSP70.

Localization

Cytosol: UniProt "Cytoplasm" (PMID:18837411); HPA IDA cytosol; GOA cytosol IDA PMID:21231916.
Z disc / sarcomere: PMID:36264506 — IDA PMID:36264506 GO:0030018 Z disc. Genuine.
Plasma membrane / cell membrane: from OPRM1 (mu opioid receptor) C-tail interaction
(PMID:16542645, yeast two-hybrid + in vitro). Membrane association is indirect (via client).
Nucleoplasm: HPA IDA only; weak, not central.

Disease: chaperonopathy / myopathy

PMID:36264506
PMID:36264506 — implies role in myofibril/Z-disc maintenance.
R25Q variant: loss of function in chaperone-mediated protein folding (UniProt VARIANT note).

Interactions (high-throughput / specific)

OPRM1 C-tail (PMID:16542645) — specific Y2H+in vitro.
SDIM1 (PMID:21255413).
HTT (P42858), ATXN1 (P54253), RUVBL2 (Q9Y230) — IntAct; aggregation-prone clients / HT.
GO:0005515 protein binding IPI PMID:32296183 (RUVBL2), PMID:32814053 (HTT, ATXN1). These are
consistent with handling aggregation-prone clients but are bare protein-binding HT calls.

Likely over-annotation

GO:0000122 negative regulation of transcription by RNA polymerase II IBA (from PANTHER
PTN008393908 / UniProtKB:P25685 = yeast Sis1/DnaJ family). No direct evidence DNAJB4 regulates
pol II transcription in human; transferred phylogenetically. MARK_AS_OVER_ANNOTATED.

MF/BP assignment summary

Core MF: GO:0001671 ATPase activator activity (HSP70 ATPase stimulation), GO:0051087 chaperone binding.
GO:0051082 unfolded protein binding (IBA, in DR line) — plausible client-binding holdase function.
GO:0006457 protein folding: downstream BP, KEEP_AS_NON_CORE (co-chaperone assists HSP70, not foldase).

Pn Notes

(DNAJB4-pn-notes.md)

DNAJB4 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9UDY4
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/DNAJB4/DNAJB4-ai-review.yaml
AIGR review HTML: present - genes/human/DNAJB4/DNAJB4-ai-review.html
Gene notes: present - genes/human/DNAJB4/DNAJB4-notes.md
GOA TSV: present - genes/human/DNAJB4/DNAJB4-goa.tsv
UniProt record: present - genes/human/DNAJB4/DNAJB4-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/DNAJB4.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/DNAJB4.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: 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.
Existing/core annotation action counts: ACCEPT: 11; KEEP_AS_NON_CORE: 12; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

Consistency: Strong agreement. Notes, review YAML and PN annotation all describe a cytosolic class-B HSP40 that stimulates HSP70 (HSPA1A/B) ATPase and delivers misfolded clients. No contradictions; PN "J-domain HSP70 cochaperone" type matches the gene's verified core MF.
PN story / NEW pressure: PN asserts direct HSP70 interaction. This is already captured experimentally: GO:0001671 ATPase activator activity (IDA, PMID:24318877, ACCEPT/core) and GO:0051087 protein-folding chaperone binding (IPI PMID:21231916, ACCEPT/core). The PN-projected GO:0030544 "Hsp70 protein binding" (verified real via OLS) is a child of GO:0051087 — i.e. it would be a more specific refinement, not a missing function. No NEW-term pressure; the muscle/Z-disc role (GO:0030018 IDA) is also well captured. Verdict: already captured (GO:0030544 is a defensible specialization).
Evidence alignment: PN reference titles overlap the review's core PMIDs (21231916 HSP70 machine; 24318877 NEF/ATPase; 36264506 myopathy/Z-disc). No divergence.
Verdict: CONSISTENT — PN GO:0030544 is a defensible narrower specialization of the gene's experimentally-supported GO:0051087/GO:0001671 HSP70-cochaperone MF; node mapping correct.

Full Consistency Review

UniProt: Q9UDY4 (HLJ1/DNAJW) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
PN placement: Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone (branch CY) ; PN-node mapping: type=mapped, scope=ok_for_propagation_to_go, GO:0030544 Hsp70 protein binding (parent group/class/branch = no_mapping)
Consistency: Strong agreement. Notes, review YAML and PN annotation all describe a cytosolic class-B HSP40 that stimulates HSP70 (HSPA1A/B) ATPase and delivers misfolded clients. No contradictions; PN "J-domain HSP70 cochaperone" type matches the gene's verified core MF.
PN story / NEW pressure: PN asserts direct HSP70 interaction. This is already captured experimentally: GO:0001671 ATPase activator activity (IDA, PMID:24318877, ACCEPT/core) and GO:0051087 protein-folding chaperone binding (IPI PMID:21231916, ACCEPT/core). The PN-projected GO:0030544 "Hsp70 protein binding" (verified real via OLS) is a child of GO:0051087 — i.e. it would be a more specific refinement, not a missing function. No NEW-term pressure; the muscle/Z-disc role (GO:0030018 IDA) is also well captured. Verdict: already captured (GO:0030544 is a defensible specialization).
Mapping strategy: Node already mapped to GO:0030544 (correct, narrower than the gene's GO:0051087). Status/scope appropriate — DNAJB4 has direct IPI HSP70-binding evidence, so it genuinely supports the type-level mapping rather than over-reaching. Parent no_mapping decisions are sound.
Evidence alignment: PN reference titles overlap the review's core PMIDs (21231916 HSP70 machine; 24318877 NEF/ATPase; 36264506 myopathy/Z-disc). No divergence.
Verdict: CONSISTENT — PN GO:0030544 is a defensible narrower specialization of the gene's experimentally-supported GO:0051087/GO:0001671 HSP70-cochaperone MF; node mapping correct.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/DNAJB4/DNAJB4-ai-review.yaml
PN workbook rows: 1

PN row 1: Cytonuclear proteostasis | Chaperone | HSP70 system | J-domain containing HSP70 cochaperone

UniProt: Q9UDY4
In branches: CY
PN-node mapping records (path + ancestors):
- [type] Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0030544 Hsp70 protein binding]
  rationale: In the PN hierarchy, this type denotes J-domain cochaperones assigned to the HSP70 system. Their shared mechanistic role is direct interaction with HSP70-family chaperones, making Hsp70 protein binding the most defensible GO target in the current cache.
- [group] Cytonuclear proteostasis|Chaperone|HSP70 system
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [class] Cytonuclear proteostasis|Chaperone
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [branch] Cytonuclear proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

GO:0030544 Hsp70 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q9UDY4
gene_symbol: DNAJB4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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).
    action: ACCEPT
    reason: The cytosol is where DNAJB4 acts as an HSP70 co-chaperone; the IBA call
      agrees with multiple experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated localization to cytoplasm, consistent with the experimentally
      supported cytosolic site of action.
    action: ACCEPT
    reason: Correct compartment for this cytosolic co-chaperone; IEA agrees with stronger
      experimental and IBA cytosol/cytoplasm evidence.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: The C-terminal section interacts with the C-terminal tail of
        OPRM1
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic annotation of protein folding, redundant with
      the IBA protein folding call and consistent with the J-protein co-chaperone role.
    action: KEEP_AS_NON_CORE
    reason: Same downstream process rationale as the IBA protein folding annotation;
      DNAJB4 assists rather than autonomously catalyzes folding.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Consistent with DNAJB4's heat-shock induction and client-handling role;
      a genuine process annotation but downstream of its molecular co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'INDUCTION: By heat shock'
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated Z-disc localization, redundant with and corroborated by the
      experimental IDA Z-disc annotation (PubMed:36264506).
    action: ACCEPT
    reason: Z-disc localization is experimentally established and central to DNAJB4's
      muscle proteostasis role; the IEA call is correct.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Cytoplasm, myofibril, sarcomere, Z line
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: Rule-based electronic annotation of chaperone binding, redundant with
      the IBA and IPI protein-folding chaperone binding annotations (binding to HSP70).
    action: ACCEPT
    reason: Correct molecular function; DNAJB4 binds HSP70, supported by stronger IPI/IBA
      evidence.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'Q9UDY4; Q9Y230: RUVBL2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'Q9UDY4; P42858: HTT'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Antibody-based nucleoplasm signal is plausible but peripheral; DNAJB4's
      characterized function is cytosolic/sarcomeric, so this is non-core.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (HPA immunofluorescence) evidence for cytosolic localization, the
      principal compartment in which DNAJB4 acts.
    action: ACCEPT
    reason: IDA-supported cytosol localization matches the documented site of co-chaperone
      action.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence plasma-membrane signal, consistent with the membrane-associated
      pool reported via the OPRM1 interaction but secondary to the cytosolic localization.
    action: KEEP_AS_NON_CORE
    reason: Plasma-membrane association of DNAJB4 is indirect/client-mediated and context-specific;
      not part of its core cytosolic chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: The C-terminal section interacts with the C-terminal tail of
        OPRM1
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:18837411
  qualifier: located_in
  review:
    summary: Experimental (antibody-based) evidence for cytoplasmic localization of
      DNAJB4/HLJ1, consistent with its cytosolic co-chaperone role.
    action: ACCEPT
    reason: Experimental cytoplasmic localization corroborates the cytosol annotations
      and the established site of action.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Cytoplasmic according to PubMed:18837411
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:16542645
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: The C-terminal section interacts with the C-terminal tail of
        OPRM1
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IDA
  original_reference_id: PMID:36264506
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Experimentally established Z-disc localization underpins DNAJB4's role in
      myofibril/Z-disc proteostasis and is supported by loss in CMYO21 patient tissue.
    supported_by:
    - reference_id: PMID:36264506
      supporting_text: DNAJB4 normally localizes to the Z-disc and was absent from
        muscle and fibroblasts of affected patients
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  qualifier: enables
  review:
    summary: Functional study of the mammalian HSP70/DNAJ machine; DNAJB4 binds HSP70
      isoforms (HSPA1A/HSPA1B) as a co-chaperone. Direct chaperone-binding evidence.
    action: ACCEPT
    reason: Binding to HSP70 chaperones is the core molecular interaction of DNAJB4
      as a J-protein co-chaperone.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-goa.tsv
      supporting_text: GO:0051087 protein-folding chaperone binding molecular_function
        ECO:0000353 IPI PMID:21231916 UniProtKB:P0DMV8
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:24318877
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: J-domain stimulation of HSP70 ATP hydrolysis is the defining molecular
      activity of DNAJB4 and is experimentally demonstrated.
    supported_by:
    - reference_id: PMID:24318877
      supporting_text: 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
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  qualifier: located_in
  review:
    summary: Direct evidence places DNAJB4 in the cytosol, consistent with all other
      localization data and its co-chaperone role.
    action: ACCEPT
    reason: IDA cytosol localization corroborates the established cytosolic site of
      action.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA PMID:21231916
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21255413
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Documented DNAJB4-SDIM1 interaction; bare protein binding is uninformative
      per curation guidelines and the interaction is peripheral to the core chaperone
      function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Also interacts with SDIM1
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: TAS
  original_reference_id: PMID:9546042
  qualifier: involved_in
  review:
    summary: The original cloning paper describes HLJ1/DNAJB4 as a heat-inducible HSP40,
      supporting a role in the response to unfolded protein.
    action: KEEP_AS_NON_CORE
    reason: Consistent with DNAJB4's stress-induced client-handling role; a genuine
      process annotation downstream of its molecular co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'INDUCTION: By heat shock'
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: TAS
  original_reference_id: PMID:9546042
  qualifier: involved_in
  review:
    summary: DNAJB4/HLJ1 is induced by heat shock, supporting involvement in the response
      to heat.
    action: KEEP_AS_NON_CORE
    reason: Heat induction is experimentally documented; participation in the heat
      response is a genuine but non-core (stress-context) process annotation.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'INDUCTION: By heat shock'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:16542645
  title: A member of the heat shock protein 40 family, hlj1, binds to the carboxyl
    tail of the human mu opioid receptor.
  findings:
  - statement: The C-terminal portion of DNAJB4/HLJ1 interacts with the C-terminal
      tail of the human mu-opioid receptor (OPRM1), conferring a membrane-associated
      pool.
    reference_section_type: RESULTS
- id: PMID:18837411
  title: Preparation of the anti-HLJ1 monoclonal antibodies and establishment of method
    for detection of the antigen.
  findings:
  - statement: DNAJB4/HLJ1 is detected in the cytoplasm.
    reference_section_type: RESULTS
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; the study characterizes
      mammalian HSP40/HSP70 co-chaperones' anti-aggregation/refolding activities.
      GOA anchors this PMID to GO:0051087 (protein-folding chaperone binding, IPI)
      and GO:0005829 (cytosol, IDA), supporting DNAJB4's core co-chaperone function.
  findings:
  - statement: DNAJB4 is a cytosolic DNAJ/HSP40 co-chaperone of the HSP70 machine with
      client-dependent refolding/anti-aggregation activities.
    reference_section_type: RESULTS
- id: PMID:21255413
  title: A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains
    and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor
    cells.
  findings:
  - statement: SDIM1 interacts with DNAJB4 and attenuates DNAJB4 over-expression-induced
      cell death in neuro-progenitor cells.
    reference_section_type: RESULTS
- id: PMID:24318877
  title: Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70)
    generates functionally distinct complexes in vitro.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; body confirms DnaJB4
      acts as a J-protein co-chaperone stimulating Hsp70 ATPase activity, and GOA
      anchors this PMID to GO:0001671 (ATPase activator activity, IDA) - the core MF.
  findings:
  - statement: DNAJB4, as a J-protein co-chaperone, stimulates HSP70 ATPase activity
      and supports luciferase refolding in combination with HSP70 and nucleotide exchange
      factors.
    reference_section_type: RESULTS
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings:
  - statement: DNAJB4 interacts with aggregation-prone neurodegeneration-associated
      clients including huntingtin (HTT) and ataxin-1 (ATXN1).
    reference_section_type: RESULTS
- id: PMID:36264506
  title: Loss of function variants in DNAJB4 cause a myopathy with early respiratory
    failure.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; body confirms biallelic
      DNAJB4 loss-of-function causes a myopathy with respiratory failure and that
      DNAJB4 localizes to the Z-disc with a role in myofibril proteostasis. GOA
      anchors this PMID to GO:0030018 (Z disc, IDA), supporting the in-vivo function.
  findings:
  - statement: Biallelic loss-of-function DNAJB4 variants cause an autosomal recessive
      myopathy with early respiratory failure (CMYO21).
    reference_section_type: RESULTS
  - statement: DNAJB4 normally localizes to the Z-disc and is absent from patient muscle
      and fibroblasts; knockout muscle accumulates Z-disc proteins and chaperones,
      indicating a role in myofibril/Z-disc proteostasis.
    reference_section_type: RESULTS
- id: PMID:9546042
  title: Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from
    human liver.
  findings:
  - statement: HLJ1/DNAJB4 is a 337-residue human HSP40/DnaJ-like protein that is induced
      by heat shock.
    reference_section_type: RESULTS
core_functions:
- description: J-domain co-chaperone that stimulates the ATPase activity of HSP70 (HSPA1A/HSPA1B),
    driving HSP70-mediated folding, refolding and disaggregation of client proteins.
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:24318877
    supporting_text: 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
  - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
    supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
      mediated by HSPA1A/B
- description: Binds the HSP70 chaperone and misfolded/aggregation-prone client proteins,
    recruiting clients to HSP70 for folding; in striated muscle this supports myofibril
    and Z-disc proteostasis.
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0030018
    label: Z disc
  supported_by:
  - reference_id: PMID:36264506
    supporting_text: DNAJB4 normally localizes to the Z-disc and was absent from muscle
      and fibroblasts of affected patients
  - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
    supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
      mediated by HSPA1A/B
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
suggested_experiments:
- description: Affinity purification-mass spectrometry of tagged DNAJB4 from muscle
    cells (with HSP70 as co-bait) to define its client interactome and compare with
    DNAJB6.
- description: 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.

DNAJB4

Gene Description