DNAJC25 (DnaJ homolog subfamily C member 25) is a poorly characterized multi-pass membrane protein of the HSP40/DnaJ co-chaperone family. It has an N-terminal signal-anchor/transmembrane segment followed by a J-domain bearing the canonical HPD tripeptide, plus additional predicted transmembrane helices. The J-domain is the module by which DnaJ proteins recruit and stimulate HSP70-family ATPases. By phylogenetic inference within its protein family, DNAJC25 is predicted to act at the endoplasmic reticulum membrane as a co-chaperone that assists HSP70-dependent protein folding/quality control, although no direct experimental functional data exist for the human protein. It is tissue-enriched in liver.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005789
endoplasmic reticulum membrane
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Phylogenetic inference places DNAJC25 at the ER membrane, consistent with its multi-pass membrane topology and membership in a family of membrane J-proteins. UniProt records only the generic 'membrane' localization for the human protein, so the specific ER-membrane assignment rests on orthology.
Reason: The ER-membrane localization is an IBA inference; the human protein is experimentally documented only as a multi-pass membrane protein without a confirmed compartment. Plausible but not directly supported, so retained as non-core.
Supporting Evidence:
file:human/DNAJC25/DNAJC25-uniprot.txt
SUBCELLULAR LOCATION: Membrane
|
|
GO:0006457
protein folding
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: As a J-domain protein, DNAJC25 is inferred to participate in HSP70-assisted protein folding. J-proteins are co-chaperones that assist HSP70 rather than autonomously folding clients. The falcon deep-research synthesis reaches the same conclusion as a family-level (not gene-specific) inference.
Reason: Protein folding is a generic downstream process of the HSP70 system that a J-domain co-chaperone assists; it is inferred from the J-domain and family membership and is non-core relative to the (uncharacterized) specific molecular co-chaperone function. The falcon report explicitly notes this is an inference from family membership ("Specific client proteins for DNAJC25 have not been experimentally identified") and is itself ungrounded synthesis, so it adds no independent experimental weight, only corroborating the family-level framing.
Supporting Evidence:
file:human/DNAJC25/DNAJC25-uniprot.txt
DOMAIN 49..124
file:human/DNAJC25/DNAJC25-deep-research-falcon.md
J-domain proteins stimulate HSP70 ATPase activity to facilitate protein folding and quality control. DNAJC25 does not have intrinsic enzymatic activity but would modulate HSP70 function.
|
|
GO:0006457
protein folding
|
IEA
GO_REF:0000002 |
KEEP AS NON CORE |
Summary: InterPro2GO electronic annotation of protein folding, derived from the DnaJ-domain signature. Duplicates the IBA protein-folding annotation.
Reason: Domain-based IEA for the generic protein-folding process; same rationale as the IBA annotation, a downstream HSP70-assisted process rather than the gene's specific molecular function.
Supporting Evidence:
file:human/DNAJC25/DNAJC25-uniprot.txt
DOMAIN 49..124
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: Membrane localization from the UniProt subcellular location, the only experimentally grounded localization (a multi-pass membrane protein). Consistent with the more specific ER-membrane IBA inference.
Reason: DNAJC25 is documented as a multi-pass membrane protein; the generic membrane localization is correct, though the specific membrane compartment remains to be established.
Supporting Evidence:
file:human/DNAJC25/DNAJC25-uniprot.txt
Multi-pass membrane protein
|
Q: At which membrane (ER, plasma membrane, other) does DNAJC25 actually reside, and does its J-domain stimulate a specific HSP70 paralog (e.g. BiP/HSPA5 for an ER protein)?
Q: What is the physiological client repertoire and biological process of DNAJC25, given its liver-enriched expression?
Experiment: Determine DNAJC25 subcellular localization by immunofluorescence/organelle fractionation and membrane topology mapping to confirm or refute the predicted ER-membrane assignment.
Experiment: Test J-domain-dependent stimulation of candidate HSP70 ATPases (BiP/HSPA5, HSPA8) in vitro using wild-type versus HPD-motif (QPD) mutant DNAJC25.
Experiment: Affinity purification-mass spectrometry of tagged DNAJC25 in liver-derived cells to identify HSP70 partners and physiological clients, and CRISPR knockout to define its biological process.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Warning: no contexts were retrieved, so this answer is not grounded in evidence but is instead a direct response from the agent model.
After conducting extensive literature searches across multiple databases, I must report that DNAJC25 (UniProt Q9H1X3, human DnaJ homolog subfamily C member 25) is an extremely poorly characterized protein with essentially no dedicated experimental studies available in the accessible scientific literature.
What can be stated based on available information:
The gene symbol DNAJC25 correctly identifies the human protein and is unambiguous. According to the UniProt data you provided, DNAJC25 contains a DnaJ domain (IPR001623) and belongs to the DNAJC25 family.
Inferred function from domain/family information:
The presence of a conserved DnaJ domain suggests DNAJC25 likely functions as a co-chaperone for Hsp70 proteins. J-domain proteins typically work with Hsp70 chaperones in protein quality control processes, including protein folding, refolding of misfolded proteins, and directing proteins toward degradation pathways. The DnaJ domain typically stimulates Hsp70's ATPase activity and helps deliver substrate proteins to Hsp70.
Critical caveat: This functional assignment is purely inferential, based on the conserved domain structure and general properties of the J-domain protein family. No experimental studies have directly demonstrated that DNAJC25 possesses co-chaperone activity, interacts with Hsp70, or has any specific client proteins.
Current state of knowledge:
Literature searches revealed no dedicated studies on DNAJC25's biochemical activity, subcellular localization, tissue expression, client protein specificity, or physiological roles. The protein represents a significant research gap in the J-domain protein field.
Conclusion:
Based solely on domain and family information, DNAJC25 can be annotated as a putative Hsp70 co-chaperone involved in protein quality control. However, this annotation lacks direct experimental support and should be considered provisional until functional studies are performed.
Poorly characterized multi-pass membrane protein of the HSP40/DnaJ co-chaperone
family; liver-enriched.
*-deep-research*.md file found in this gene directory.Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone ; PN-node mapping: type=mapped, scope=ok_for_propagation_to_go, GO:0030544 Hsp70 protein binding (projected new_to_goa); group/class/branch=no_mapping.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.
id: Q9H1X3
gene_symbol: DNAJC25
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: DNAJC25 (DnaJ homolog subfamily C member 25) is a poorly characterized
multi-pass membrane protein of the HSP40/DnaJ co-chaperone family. It has an N-terminal
signal-anchor/transmembrane segment followed by a J-domain bearing the canonical
HPD tripeptide, plus additional predicted transmembrane helices. The J-domain is
the module by which DnaJ proteins recruit and stimulate HSP70-family ATPases. By
phylogenetic inference within its protein family, DNAJC25 is predicted to act at
the endoplasmic reticulum membrane as a co-chaperone that assists HSP70-dependent
protein folding/quality control, although no direct experimental functional data
exist for the human protein. It is tissue-enriched in liver.
alternative_products:
- name: '1'
id: Q9H1X3-1
- name: '2'
id: Q9H1X3-2
sequence_note: VSP_035180
- name: '3'
id: Q9H1X3-3
sequence_note: VSP_035181, VSP_035182
existing_annotations:
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: Phylogenetic inference places DNAJC25 at the ER membrane, consistent
with its multi-pass membrane topology and membership in a family of membrane
J-proteins. UniProt records only the generic 'membrane' localization for the
human protein, so the specific ER-membrane assignment rests on orthology.
action: KEEP_AS_NON_CORE
reason: The ER-membrane localization is an IBA inference; the human protein is
experimentally documented only as a multi-pass membrane protein without a confirmed
compartment. Plausible but not directly supported, so retained as non-core.
supported_by:
- reference_id: file:human/DNAJC25/DNAJC25-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Membrane'
- term:
id: GO:0006457
label: protein folding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: As a J-domain protein, DNAJC25 is inferred to participate in HSP70-assisted
protein folding. J-proteins are co-chaperones that assist HSP70 rather than
autonomously folding clients. The falcon deep-research synthesis reaches the
same conclusion as a family-level (not gene-specific) inference.
action: KEEP_AS_NON_CORE
reason: Protein folding is a generic downstream process of the HSP70 system that
a J-domain co-chaperone assists; it is inferred from the J-domain and family
membership and is non-core relative to the (uncharacterized) specific molecular
co-chaperone function. The falcon report explicitly notes this is an inference
from family membership ("Specific client proteins for DNAJC25 have not been
experimentally identified") and is itself ungrounded synthesis, so it adds no
independent experimental weight, only corroborating the family-level framing.
supported_by:
- reference_id: file:human/DNAJC25/DNAJC25-uniprot.txt
supporting_text: DOMAIN 49..124
- reference_id: file:human/DNAJC25/DNAJC25-deep-research-falcon.md
supporting_text: J-domain proteins stimulate HSP70 ATPase activity to facilitate
protein folding and quality control. DNAJC25 does not have intrinsic enzymatic
activity but would modulate HSP70 function.
- term:
id: GO:0006457
label: protein folding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: InterPro2GO electronic annotation of protein folding, derived from the
DnaJ-domain signature. Duplicates the IBA protein-folding annotation.
action: KEEP_AS_NON_CORE
reason: Domain-based IEA for the generic protein-folding process; same rationale
as the IBA annotation, a downstream HSP70-assisted process rather than the gene's
specific molecular function.
supported_by:
- reference_id: file:human/DNAJC25/DNAJC25-uniprot.txt
supporting_text: DOMAIN 49..124
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: Membrane localization from the UniProt subcellular location, the only
experimentally grounded localization (a multi-pass membrane protein). Consistent
with the more specific ER-membrane IBA inference.
action: ACCEPT
reason: DNAJC25 is documented as a multi-pass membrane protein; the generic membrane
localization is correct, though the specific membrane compartment remains to
be established.
supported_by:
- reference_id: file:human/DNAJC25/DNAJC25-uniprot.txt
supporting_text: Multi-pass membrane protein
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: file:human/DNAJC25/DNAJC25-uniprot.txt
title: UniProt entry Q9H1X3 (DJC25_HUMAN), DnaJ homolog subfamily C member 25
findings:
- statement: Multi-pass membrane protein of the DnaJ/HSP40 family with a J-domain;
no experimentally characterized molecular function; predicted ER-membrane co-chaperone.
reference_section_type: OTHER
- id: file:human/DNAJC25/DNAJC25-deep-research-falcon.md
title: Falcon deep research report for DNAJC25
findings: []
reference_review:
relevance: MEDIUM
correctness: UNVERIFIED
review_notes: 'LLM-synthesized deep-research report. The report itself warns "no
contexts were retrieved, so this answer is not grounded in evidence" and that
evidence gathering "experienced technical difficulties". SAFE, family-level claims
that are usable: DNAJC25 is a J-domain/HSP40 protein inferred to act as an HSP70
co-chaperone (stimulating HSP70 ATPase to assist protein folding/quality control)
with no intrinsic enzymatic activity and no experimentally identified clients
— this only corroborates the existing IBA/IEA framing and adds no independent
experimental weight. SPECULATIVE / NOT incorporated: (1) cytoplasmic localization
(attributed to "review literature discussing DNAJC subfamily members", not to
DNAJC25 directly, and it contradicts the UniProt multi-pass membrane / IBA ER-membrane
evidence); (2) RNF149 substrate / hepatocellular-carcinoma tumor-suppressor role
(Guo et al. 2023, cancers15215203) — a gene-specific functional claim drawn from
an abstract in an ungrounded report and not independently verified here, so not
added to existing_annotations or core_functions. Cited DOIs were not PubMed-verified
in this review.'
core_functions:
- description: Predicted membrane-anchored HSP40/J-domain co-chaperone that, via its
HPD-bearing J-domain, would recruit and stimulate HSP70-family chaperones to assist
protein folding/quality control at a cellular membrane (inferred to be the ER
membrane). No direct experimental evidence exists for the human protein.
molecular_function:
id: GO:0031072
label: heat shock protein binding
locations:
- id: GO:0016020
label: membrane
supported_by:
- reference_id: file:human/DNAJC25/DNAJC25-uniprot.txt
supporting_text: DOMAIN 49..124
- reference_id: file:human/DNAJC25/DNAJC25-uniprot.txt
supporting_text: Multi-pass membrane protein
proposed_new_terms: []
suggested_questions:
- question: At which membrane (ER, plasma membrane, other) does DNAJC25 actually reside,
and does its J-domain stimulate a specific HSP70 paralog (e.g. BiP/HSPA5 for an
ER protein)?
- question: What is the physiological client repertoire and biological process of
DNAJC25, given its liver-enriched expression?
suggested_experiments:
- description: Determine DNAJC25 subcellular localization by immunofluorescence/organelle
fractionation and membrane topology mapping to confirm or refute the predicted
ER-membrane assignment.
- description: Test J-domain-dependent stimulation of candidate HSP70 ATPases (BiP/HSPA5,
HSPA8) in vitro using wild-type versus HPD-motif (QPD) mutant DNAJC25.
- description: Affinity purification-mass spectrometry of tagged DNAJC25 in liver-derived
cells to identify HSP70 partners and physiological clients, and CRISPR knockout
to define its biological process.