id: O75165 gene_symbol: DNAJC13 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: DNAJC13 (RME-8, "Required for receptor-mediated endocytosis 8") is a large (2243 aa) multidomain DnaJ/HSP40 subfamily C protein that acts as an endosomal co-chaperone of the HSC70 (HSPA8) chaperone. It is a peripheral membrane protein associated with early endosomes via its N-terminal region and carries an internal J domain (residues 1301-1366) that stimulates the ATPase activity of HSC70 to drive clathrin dynamics on endosomal membranes. Through this activity DNAJC13 regulates endosomal protein sorting and membrane trafficking, including transferrin recycling (early endosome to recycling endosome transport) and EGF/EGFR degradation (early endosome to late endosome transport). It binds the WASH complex subunit WASHC2/FAM21 and the sorting nexin SNX1, coordinating WASH complex activity with retromer-dependent endosomal membrane tubulation. DNAJC13 variants have been implicated in autosomal-dominant Parkinson disease (PARK21). existing_annotations: - term: id: GO:0006898 label: receptor-mediated endocytosis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic (IBA) annotation reflecting the gene's historical name (RME-8, required for receptor-mediated endocytosis), originally defined in C. elegans yolk uptake. In human cells DNAJC13/RME-8 acts on early endosomes downstream of internalization (sorting, recycling and degradation) rather than at the plasma-membrane internalization step per se, so this is a broadly correct but non-core process annotation. action: KEEP_AS_NON_CORE reason: The family-level receptor-mediated endocytosis term is supported by orthology and the gene's role in endocytic trafficking, but DNAJC13's documented site of action is the endosome (recycling and degradative sorting), not the internalization step; it is a peripheral process relative to its core endosomal co-chaperone function. supported_by: - reference_id: PMID:18256511 supporting_text: hRME is primarily involved in membrane trafficking through early endosomes, but not through degradative organelles, such as multivesicular bodies and late endosomes. - term: id: GO:0005769 label: early endosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated SubCell localization to early endosome, redundant with and consistent with the experimentally supported (EXP/IDA) early-endosome localization. action: ACCEPT reason: DNAJC13 partially colocalizes with early endosomal markers and is its principal site of action; the IEA term agrees with stronger experimental evidence. supported_by: - reference_id: PMID:18256511 supporting_text: It partially colocalized with several early endosomal markers, but not with late endosomal markers - term: id: GO:0007032 label: endosome organization evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro2GO electronic annotation of endosome organization, redundant with the experimentally supported IMP annotation of the same term (PMID:24643499); DNAJC13 controls endosomal membrane tubulation and SNX1 dynamics. action: ACCEPT reason: Corroborated by direct experimental evidence that loss of DNAJC13/RME-8 alters endosomal tubulation and SNX1 membrane association; a core biological process for this gene. supported_by: - reference_id: PMID:24643499 supporting_text: Loss of RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly branched endosomal tubules. - term: id: GO:0010008 label: endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated SubCell localization to endosome membrane, redundant with the experimentally supported (IDA) endosome-membrane localization. action: ACCEPT reason: DNAJC13 is a peripheral endosome-membrane protein; consistent with IDA evidence. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-uniprot.txt supporting_text: Endosome membrane {ECO:0000269|PubMed:24643499}. - term: id: GO:0031901 label: early endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated SubCell localization to early endosome membrane, redundant with the experimentally supported (IDA) annotation of the same term. action: ACCEPT reason: DNAJC13 associates peripherally with early endosome membranes; agrees with IDA evidence. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-uniprot.txt supporting_text: Early endosome membrane {ECO:0000305}; Peripheral membrane protein - term: id: GO:2000641 label: regulation of early endosome to late endosome transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro2GO electronic annotation, redundant with the experimentally supported IMP annotation of the same term; DNAJC13 regulates EGF/EGFR transit toward degradation. action: ACCEPT reason: Supported by direct evidence that DNAJC13 controls EGF/EGFR sorting from early endosomes toward the degradative pathway; a genuine process for this gene. supported_by: - reference_id: PMID:18307993 supporting_text: RME-8 depletion leads to decreased levels of epidermal growth factor receptor (EGFR) - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: High-throughput interaction capturing the DNAJC13-SCAMP1 (O15126) interaction also recorded in the UniProt INTERACTION block. The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (with SCAMP1, a secretory carrier membrane protein) but GO:0005515 is uninformative and not part of the core endosomal co-chaperone function; not elevated to core per curation guidelines. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-uniprot.txt supporting_text: 'O75165; O15126: SCAMP1; NbExp=3; IntAct=EBI-4324603, EBI-954338;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification interactome capturing the DNAJC13-SCAMP1 (O15126) interaction. The bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Real but uninformative high-throughput interaction (SCAMP1); not core and not elevated per curation guidelines. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-uniprot.txt supporting_text: 'O75165; O15126: SCAMP1; NbExp=3; IntAct=EBI-4324603, EBI-954338;' - term: id: GO:0005769 label: early endosome evidence_type: EXP original_reference_id: PMID:18256511 qualifier: located_in review: summary: Experimental (EXP) localization of DNAJC13/RME-8 to early endosomes by colocalization with early endosomal markers and immunoelectron microscopy. action: ACCEPT reason: Direct experimental evidence places DNAJC13 at early endosomes, its principal site of action; a core cellular-component annotation. supported_by: - reference_id: PMID:18256511 supporting_text: It partially colocalized with several early endosomal markers, but not with late endosomal markers, consistent with observations by immunoelectron microscopy. - term: id: GO:0001649 label: osteoblast differentiation evidence_type: HDA original_reference_id: PMID:16210410 qualifier: involved_in review: summary: Annotation derived from a quantitative membrane-proteomics study of a mesenchymal stem-cell line undergoing osteoblast differentiation; DNAJC13 was detected as a differentially expressed membrane protein, not shown to function in osteoblast differentiation. action: MARK_AS_OVER_ANNOTATED reason: This is an expression-correlation (HDA) observation from a differentiation proteomics screen, not evidence that DNAJC13 plays a role in osteoblast differentiation; over-annotation relative to the gene's endosomal function. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0001649 osteoblast differentiation biological_process ECO:0007005 HDA PMID:16210410 - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:16210410 qualifier: located_in review: summary: High-throughput membrane-proteomics detection of DNAJC13 in a membrane fraction. A generic membrane localization consistent with its peripheral endosome-membrane association. action: KEEP_AS_NON_CORE reason: Correct but uninformative generic localization; the precise compartment (early endosome membrane) is captured by more specific annotations. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:16210410 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798739 qualifier: located_in review: summary: Reactome annotation from the neutrophil-degranulation pathway placing DNAJC13 at the plasma membrane. This reflects bulk granule/membrane proteome curation, not DNAJC13's core endosomal function. action: KEEP_AS_NON_CORE reason: Curated TAS localization from a neutrophil degranulation pathway; peripheral to and not representative of DNAJC13's principal early-endosome site of action. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0005886 plasma membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798739 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798743 qualifier: located_in review: summary: Second Reactome (neutrophil degranulation) plasma-membrane annotation, redundant with the R-HSA-6798739 entry. action: KEEP_AS_NON_CORE reason: Curated TAS localization from neutrophil degranulation; peripheral to the core endosomal function. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0005886 plasma membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798743 - term: id: GO:0030667 label: secretory granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798743 qualifier: located_in review: summary: Reactome neutrophil-degranulation annotation placing DNAJC13 in the secretory granule membrane. Reflects bulk granule-proteome curation rather than a defined granule function. action: KEEP_AS_NON_CORE reason: Curated TAS localization from a degranulation pathway; specialized context peripheral to DNAJC13's core endosomal co-chaperone role. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0030667 secretory granule membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798743 - term: id: GO:0035577 label: azurophil granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798739 qualifier: located_in review: summary: Reactome neutrophil-degranulation annotation placing DNAJC13 in the azurophil granule membrane. Reflects bulk granule-proteome curation. action: KEEP_AS_NON_CORE reason: Curated TAS localization from a degranulation pathway; specialized context peripheral to the core endosomal function. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0035577 azurophil granule membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798739 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24643499 qualifier: enables review: summary: Curated interactions with WASH-complex subunits (WASHC2C/FAM21 A8K0Z3, WASHC5/strumpellin Q12768, WASHC2A/FAM21A Q9Y4E1). The bare protein binding term is uninformative, but these interactions are biologically meaningful and underpin DNAJC13's coordination of the WASH complex with retromer. action: KEEP_AS_NON_CORE reason: Records real, functionally relevant WASH-complex interactions; however GO:0005515 itself is uninformative and is kept non-core (the functional consequence is captured by the endosome organization process annotation). supported_by: - reference_id: PMID:24643499 supporting_text: we show that FAM21 also binds to the SNX1-interacting DNAJ protein RME-8. - term: id: GO:0007032 label: endosome organization evidence_type: IMP original_reference_id: PMID:24643499 qualifier: involved_in review: summary: IMP evidence that loss of DNAJC13/RME-8 dysregulates endosomal membrane tubulation and SNX1 dynamics, demonstrating a direct role in organizing the endosomal compartment. action: ACCEPT reason: Strong loss-of-function evidence that DNAJC13 controls endosomal tubulation/SNX1 dynamics; a core biological process for this gene. supported_by: - reference_id: PMID:24643499 supporting_text: Loss of RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly branched endosomal tubules. - term: id: GO:0010008 label: endosome membrane evidence_type: IDA original_reference_id: PMID:24643499 qualifier: located_in review: summary: Direct (IDA) evidence localizing DNAJC13 to endosome membranes. action: ACCEPT reason: Direct experimental localization to the endosome membrane, the site of DNAJC13 action. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-uniprot.txt supporting_text: Endosome membrane {ECO:0000269|PubMed:24643499}. - term: id: GO:0031901 label: early endosome membrane evidence_type: IDA original_reference_id: PMID:18256511 qualifier: located_in review: summary: Direct (IDA) localization of DNAJC13/RME-8 to early endosome membranes via its N-terminal membrane-association region. action: ACCEPT reason: Direct experimental localization to the early endosome membrane; a core cellular component for this peripheral membrane protein. supported_by: - reference_id: PMID:18256511 supporting_text: hRME-8 was found to be a peripheral protein that was tightly associated with the membrane via its N-terminal region. - term: id: GO:0071203 label: WASH complex evidence_type: IDA original_reference_id: PMID:24643499 qualifier: colocalizes_with review: summary: Colocalization of DNAJC13 with the WASH complex, consistent with its binding to FAM21 (WASHC2) and its role in coordinating WASH activity with retromer-mediated sorting. action: ACCEPT reason: Supported by direct colocalization and FAM21 binding; the colocalizes_with qualifier appropriately reflects that DNAJC13 associates with, but is not a stoichiometric subunit of, the WASH complex. supported_by: - reference_id: PMID:24643499 supporting_text: we show that FAM21 also binds to the SNX1-interacting DNAJ protein RME-8. - term: id: GO:2000641 label: regulation of early endosome to late endosome transport evidence_type: IMP original_reference_id: PMID:18256511 qualifier: involved_in review: summary: IMP evidence that C-terminal truncation of DNAJC13/RME-8 compromises the degradative pathway for EGF/EGFR (early endosome to late endosome transport). action: ACCEPT reason: Loss-of-function evidence that DNAJC13 regulates trafficking of cargo from early endosomes toward degradation; a core process for this gene. supported_by: - reference_id: PMID:18256511 supporting_text: compromised endocytic pathways through early endosomes, i.e., recycling of transferrin and degradation of epidermal growth factor. - term: id: GO:2001135 label: regulation of endocytic recycling evidence_type: IMP original_reference_id: PMID:18256511 qualifier: involved_in review: summary: IMP evidence that DNAJC13/RME-8 regulates transferrin recycling (early endosome to recycling endosome transport). action: ACCEPT reason: Loss-of-function evidence that DNAJC13 controls endocytic recycling of transferrin; a core process for this gene. supported_by: - reference_id: PMID:18256511 supporting_text: compromised endocytic pathways through early endosomes, i.e., recycling of transferrin and degradation of epidermal growth factor. - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: High-throughput proteomics detection of DNAJC13 in a membrane fraction; generic localization consistent with its peripheral membrane association. action: KEEP_AS_NON_CORE reason: Correct but uninformative generic localization superseded by specific early-endosome membrane annotations. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888 - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Detection of DNAJC13 in an extracellular-exosome proteomics dataset. Consistent with its endosomal localization (exosomes derive from endosomes) but does not denote a functional exosomal role. action: KEEP_AS_NON_CORE reason: Bulk exosome-proteomics detection; plausible given endosomal origin of exosomes but peripheral to the gene's core function. supported_by: - reference_id: file:human/DNAJC13/DNAJC13-goa.tsv supporting_text: GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19056867 - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: High-throughput lysosomal-membrane proteomics detection of DNAJC13. DNAJC13 acts on early endosomes and is explicitly reported NOT to act on degradative organelles, so this is likely contamination/co-fractionation rather than a genuine lysosomal pool. action: MARK_AS_OVER_ANNOTATED reason: DNAJC13/RME-8 colocalizes with early but not late/degradative endosomal markers; a lysosomal-membrane localization from bulk proteomics conflicts with the experimental site of action and is likely co-fractionation. supported_by: - reference_id: PMID:18256511 supporting_text: It partially colocalized with several early endosomal markers, but not with late endosomal markers 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: PMID:16210410 title: Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation. findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: [] - id: PMID:18256511 title: Human RME-8 is involved in membrane trafficking through early endosomes. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached publication title matches PubMed; body confirms DNAJC13/RME-8 localizes to early endosomes and is required for transferrin recycling and EGFR trafficking. GOA anchors this PMID to GO:0005769/GO:0031901 (early endosome, EXP/IDA) and GO:2001135/GO:2000641 (IMP), supporting the core role. findings: - statement: DNAJC13/RME-8 is a peripheral membrane protein associated via its N-terminal region, colocalizing with early but not late endosomal markers; C-terminal truncation compromises transferrin recycling and EGF/EGFR degradation. reference_section_type: RESULTS - id: PMID:18307993 title: RME-8 regulates trafficking of the epidermal growth factor receptor. findings: - statement: RME-8 depletion decreases EGFR via increased degradation, implicating RME-8 in endosomal sorting decisions affecting EGFR. reference_section_type: RESULTS - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:24643499 title: RME-8 coordinates the activity of the WASH complex with the function of the retromer SNX dimer to control endosomal tubulation. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached publication title matches PubMed; body confirms DNAJC13/RME-8 binds FAM21/WASH and coordinates retromer SNX1 to control endosomal tubulation. GOA anchors this PMID to GO:0071203 (WASH complex, IDA), GO:0007032 (endosome organization, IMP) and GO:0010008, supporting the core endosomal-sorting role. findings: - statement: FAM21 (WASHC2) binds the SNX1-interacting DNAJ protein RME-8; loss of RME-8 alters SNX1 membrane-association kinetics and causes excessive branched endosomal tubules. reference_section_type: RESULTS - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: Reactome:R-HSA-6798739 title: Neutrophil degranulation (azurophil granule) findings: [] - id: Reactome:R-HSA-6798743 title: Neutrophil degranulation (secretory granule / plasma membrane) findings: [] - id: file:human/DNAJC13/DNAJC13-uniprot.txt title: UniProt entry O75165 (DJC13_HUMAN), DnaJ homolog subfamily C member 13 / RME-8 findings: - statement: Involved in membrane trafficking through early endosomes (transferrin recycling and EGF/EGFR degradation); regulates endosomal membrane tubulation and SNX1 dynamics; binds WASHC2 to link the WASH complex to the retromer SNX-BAR subcomplex; peripheral early-endosome membrane protein with an internal J domain. reference_section_type: OTHER core_functions: - description: Endosomal HSC70 (HSPA8) co-chaperone whose internal J domain stimulates HSC70 ATPase activity to drive clathrin dynamics and protein sorting on early endosome membranes. molecular_function: id: GO:0001671 label: ATPase activator activity locations: - id: GO:0031901 label: early endosome membrane supported_by: - reference_id: file:human/DNAJC13/DNAJC13-uniprot.txt supporting_text: Early endosome membrane {ECO:0000305}; Peripheral membrane protein - reference_id: PMID:18256511 supporting_text: hRME-8 was found to be a peripheral protein that was tightly associated with the membrane via its N-terminal region. - description: Regulator of endosomal organization and protein sorting that controls endosomal membrane tubulation, SNX1 dynamics and cargo fate (transferrin recycling versus EGF/EGFR degradation), in part by linking the WASH complex (via FAM21/WASHC2) to the retromer SNX dimer. molecular_function: id: GO:0001671 label: ATPase activator activity locations: - id: GO:0005769 label: early endosome supported_by: - reference_id: PMID:24643499 supporting_text: Loss of RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly branched endosomal tubules. - reference_id: PMID:18256511 supporting_text: compromised endocytic pathways through early endosomes, i.e., recycling of transferrin and degradation of epidermal growth factor. directly_involved_in: - id: GO:0007032 label: endosome organization proposed_new_terms: [] suggested_questions: - question: Does the J domain of DNAJC13/RME-8 stimulate HSC70 ATPase activity directly on endosomal clathrin, and is this required for the SNX1-dynamics and tubulation phenotypes? - question: Are the Parkinson-disease-associated DNAJC13 variants (e.g. p.Asn855Ser) genuinely pathogenic via altered endosomal sorting, given the co-segregating TMEM230 variants in the same family? suggested_experiments: - description: Reconstitute DNAJC13 J-domain-stimulated HSC70 ATPase and clathrin-uncoating activity in vitro, using a J-domain HPD-motif mutant as a negative control, to test whether the co-chaperone activity drives endosomal clathrin dynamics. - description: Knock-in of Parkinson-associated DNAJC13 variants in iPSC-derived dopaminergic neurons with live-cell imaging of transferrin recycling, EGFR degradation and SNX1/retromer tubulation to assess functional consequences.