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.