Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006898 receptor-mediated endocytosis	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:18256511 hRME is primarily involved in membrane trafficking through early endosomes, but not through degradative organelles, such as multivesicular bodies and late endosomes.
GO:0005769 early endosome	IEA GO_REF:0000044	ACCEPT	Summary: Automated SubCell localization to early endosome, redundant with and consistent with the experimentally supported (EXP/IDA) early-endosome localization. Reason: DNAJC13 partially colocalizes with early endosomal markers and is its principal site of action; the IEA term agrees with stronger experimental evidence. Supporting Evidence: PMID:18256511 It partially colocalized with several early endosomal markers, but not with late endosomal markers
GO:0007032 endosome organization	IEA GO_REF:0000002	ACCEPT	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. 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. Supporting Evidence: PMID:24643499 Loss of RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly branched endosomal tubules.
GO:0010008 endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: Automated SubCell localization to endosome membrane, redundant with the experimentally supported (IDA) endosome-membrane localization. Reason: DNAJC13 is a peripheral endosome-membrane protein; consistent with IDA evidence. Supporting Evidence: file:human/DNAJC13/DNAJC13-uniprot.txt Endosome membrane {ECO:0000269\|PubMed:24643499}.
GO:0031901 early endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: Automated SubCell localization to early endosome membrane, redundant with the experimentally supported (IDA) annotation of the same term. Reason: DNAJC13 associates peripherally with early endosome membranes; agrees with IDA evidence. Supporting Evidence: file:human/DNAJC13/DNAJC13-uniprot.txt Early endosome membrane {ECO:0000305}; Peripheral membrane protein
GO:2000641 regulation of early endosome to late endosome transport	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation, redundant with the experimentally supported IMP annotation of the same term; DNAJC13 regulates EGF/EGFR transit toward degradation. Reason: Supported by direct evidence that DNAJC13 controls EGF/EGFR sorting from early endosomes toward the degradative pathway; a genuine process for this gene. Supporting Evidence: PMID:18307993 RME-8 depletion leads to decreased levels of epidermal growth factor receptor (EGFR)
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: High-throughput interaction capturing the DNAJC13-SCAMP1 (O15126) interaction also recorded in the UniProt INTERACTION block. The bare protein binding term is uninformative. 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. Supporting Evidence: file:human/DNAJC13/DNAJC13-uniprot.txt O75165; O15126: SCAMP1; NbExp=3; IntAct=EBI-4324603, EBI-954338;
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex affinity-purification interactome capturing the DNAJC13-SCAMP1 (O15126) interaction. The bare protein binding term is uninformative. Reason: Real but uninformative high-throughput interaction (SCAMP1); not core and not elevated per curation guidelines. Supporting Evidence: file:human/DNAJC13/DNAJC13-uniprot.txt O75165; O15126: SCAMP1; NbExp=3; IntAct=EBI-4324603, EBI-954338;
GO:0005769 early endosome	EXP PMID:18256511 Human RME-8 is involved in membrane trafficking through earl...	ACCEPT	Summary: Experimental (EXP) localization of DNAJC13/RME-8 to early endosomes by colocalization with early endosomal markers and immunoelectron microscopy. Reason: Direct experimental evidence places DNAJC13 at early endosomes, its principal site of action; a core cellular-component annotation. Supporting Evidence: PMID:18256511 It partially colocalized with several early endosomal markers, but not with late endosomal markers, consistent with observations by immunoelectron microscopy.
GO:0001649 osteoblast differentiation	HDA PMID:16210410 Differential expression profiling of membrane proteins by qu...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0001649 osteoblast differentiation biological_process ECO:0007005 HDA PMID:16210410
GO:0016020 membrane	HDA PMID:16210410 Differential expression profiling of membrane proteins by qu...	KEEP AS NON CORE	Summary: High-throughput membrane-proteomics detection of DNAJC13 in a membrane fraction. A generic membrane localization consistent with its peripheral endosome-membrane association. Reason: Correct but uninformative generic localization; the precise compartment (early endosome membrane) is captured by more specific annotations. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:16210410
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798739	KEEP AS NON CORE	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. Reason: Curated TAS localization from a neutrophil degranulation pathway; peripheral to and not representative of DNAJC13's principal early-endosome site of action. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0005886 plasma membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798739
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798743	KEEP AS NON CORE	Summary: Second Reactome (neutrophil degranulation) plasma-membrane annotation, redundant with the R-HSA-6798739 entry. Reason: Curated TAS localization from neutrophil degranulation; peripheral to the core endosomal function. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0005886 plasma membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798743
GO:0030667 secretory granule membrane	TAS Reactome:R-HSA-6798743	KEEP AS NON CORE	Summary: Reactome neutrophil-degranulation annotation placing DNAJC13 in the secretory granule membrane. Reflects bulk granule-proteome curation rather than a defined granule function. Reason: Curated TAS localization from a degranulation pathway; specialized context peripheral to DNAJC13's core endosomal co-chaperone role. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0030667 secretory granule membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798743
GO:0035577 azurophil granule membrane	TAS Reactome:R-HSA-6798739	KEEP AS NON CORE	Summary: Reactome neutrophil-degranulation annotation placing DNAJC13 in the azurophil granule membrane. Reflects bulk granule-proteome curation. Reason: Curated TAS localization from a degranulation pathway; specialized context peripheral to the core endosomal function. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0035577 azurophil granule membrane cellular_component ECO:0000304 TAS Reactome:R-HSA-6798739
GO:0005515 protein binding	IPI PMID:24643499 RME-8 coordinates the activity of the WASH complex with the ...	KEEP AS NON CORE	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. 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). Supporting Evidence: PMID:24643499 we show that FAM21 also binds to the SNX1-interacting DNAJ protein RME-8.
GO:0007032 endosome organization	IMP PMID:24643499 RME-8 coordinates the activity of the WASH complex with the ...	ACCEPT	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. Reason: Strong loss-of-function evidence that DNAJC13 controls endosomal tubulation/SNX1 dynamics; a core biological process for this gene. Supporting Evidence: PMID:24643499 Loss of RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly branched endosomal tubules.
GO:0010008 endosome membrane	IDA PMID:24643499 RME-8 coordinates the activity of the WASH complex with the ...	ACCEPT	Summary: Direct (IDA) evidence localizing DNAJC13 to endosome membranes. Reason: Direct experimental localization to the endosome membrane, the site of DNAJC13 action. Supporting Evidence: file:human/DNAJC13/DNAJC13-uniprot.txt Endosome membrane {ECO:0000269\|PubMed:24643499}.
GO:0031901 early endosome membrane	IDA PMID:18256511 Human RME-8 is involved in membrane trafficking through earl...	ACCEPT	Summary: Direct (IDA) localization of DNAJC13/RME-8 to early endosome membranes via its N-terminal membrane-association region. Reason: Direct experimental localization to the early endosome membrane; a core cellular component for this peripheral membrane protein. Supporting Evidence: PMID:18256511 hRME-8 was found to be a peripheral protein that was tightly associated with the membrane via its N-terminal region.
GO:0071203 WASH complex	IDA PMID:24643499 RME-8 coordinates the activity of the WASH complex with the ...	ACCEPT	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. 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. Supporting Evidence: PMID:24643499 we show that FAM21 also binds to the SNX1-interacting DNAJ protein RME-8.
GO:2000641 regulation of early endosome to late endosome transport	IMP PMID:18256511 Human RME-8 is involved in membrane trafficking through earl...	ACCEPT	Summary: IMP evidence that C-terminal truncation of DNAJC13/RME-8 compromises the degradative pathway for EGF/EGFR (early endosome to late endosome transport). Reason: Loss-of-function evidence that DNAJC13 regulates trafficking of cargo from early endosomes toward degradation; a core process for this gene. Supporting Evidence: PMID:18256511 compromised endocytic pathways through early endosomes, i.e., recycling of transferrin and degradation of epidermal growth factor.
GO:2001135 regulation of endocytic recycling	IMP PMID:18256511 Human RME-8 is involved in membrane trafficking through earl...	ACCEPT	Summary: IMP evidence that DNAJC13/RME-8 regulates transferrin recycling (early endosome to recycling endosome transport). Reason: Loss-of-function evidence that DNAJC13 controls endocytic recycling of transferrin; a core process for this gene. Supporting Evidence: PMID:18256511 compromised endocytic pathways through early endosomes, i.e., recycling of transferrin and degradation of epidermal growth factor.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	KEEP AS NON CORE	Summary: High-throughput proteomics detection of DNAJC13 in a membrane fraction; generic localization consistent with its peripheral membrane association. Reason: Correct but uninformative generic localization superseded by specific early-endosome membrane annotations. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	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. Reason: Bulk exosome-proteomics detection; plausible given endosomal origin of exosomes but peripheral to the gene's core function. Supporting Evidence: file:human/DNAJC13/DNAJC13-goa.tsv GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19056867
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:18256511 It partially colocalized with several early endosomal markers, but not with late endosomal markers

Core Functions

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:

ATPase activator activity

Cellular Locations:

early endosome membrane

Supporting Evidence:

file:human/DNAJC13/DNAJC13-uniprot.txt
Early endosome membrane {ECO:0000305}; Peripheral membrane protein
PMID:18256511
hRME-8 was found to be a peripheral protein that was tightly associated with the membrane via its N-terminal region.

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:

ATPase activator activity

Directly Involved In:

endosome organization

Cellular Locations:

early endosome

Supporting Evidence:

PMID:24643499
Loss of RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly branched endosomal tubules.
PMID:18256511
compromised endocytic pathways through early endosomes, i.e., recycling of transferrin and degradation of epidermal growth factor.

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

PMID:16210410

Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation.

PMID:17897319

Integral and associated lysosomal membrane proteins.

PMID:18256511

Human RME-8 is involved in membrane trafficking through early endosomes.

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.

PMID:18307993

RME-8 regulates trafficking of the epidermal growth factor receptor.

RME-8 depletion decreases EGFR via increased degradation, implicating RME-8 in endosomal sorting decisions affecting EGFR.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:24643499

RME-8 coordinates the activity of the WASH complex with the function of the retromer SNX dimer to control endosomal tubulation.

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.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

Reactome:R-HSA-6798739

Neutrophil degranulation (azurophil granule)

Reactome:R-HSA-6798743

Neutrophil degranulation (secretory granule / plasma membrane)

file:human/DNAJC13/DNAJC13-uniprot.txt

UniProt entry O75165 (DJC13_HUMAN), DnaJ homolog subfamily C member 13 / RME-8

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.

Suggested Experiments

Experiment: 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.

Experiment: 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.

📚 Additional Documentation

Notes

(DNAJC13-notes.md)

DNAJC13 (RME-8) research notes

Identity

UniProt O75165, HGNC:30343, 2243 aa. Large multidomain DnaJ/HSP40 subfamily C protein.
AltName "Required for receptor-mediated endocytosis 8" (RME-8). Synonyms KIAA0678, RME8.
Domain architecture: N-terminal membrane-association region (1-453), multiple ARM/HEAT-like
repeats (Gene3D 1.25.10.10 x2; SUPFAM ARM repeat x3), GYF-like domain, and a single J domain
near the C-terminus (residues 1301-1366). [file:human/DNAJC13/DNAJC13-uniprot.txt]
Note: J domain is internal/C-terminal, NOT N-terminal as in canonical type-I/II HSP40s.

Core function: endosomal HSC70 co-chaperone / clathrin dynamics

Co-chaperone of HSC70 (HSPA8). The J domain stimulates HSC70 ATPase to drive clathrin uncoating
on endosomes, regulating retrieval/recycling sorting. (Established in C. elegans and conserved.)
UniProt FUNCTION: "Involved in membrane trafficking through early endosomes, such as the early
endosome to recycling endosome transport implicated in the recycling of transferrin and the early
endosome to late endosome transport implicated in degradation of EGF and EGFR ... Involved in the
regulation of endosomal membrane tubulation and regulates the dynamics of SNX1 on the endosomal
membrane; via association with WASHC2 may link the WASH complex to the retromer SNX-BAR subcomplex"
[file:human/DNAJC13/DNAJC13-uniprot.txt]

Key experimental papers

PMID:18256511 (Fujibayashi 2008): hRME-8 is a peripheral membrane protein tightly associated via
N-terminal region, colocalizes with early (not late) endosomal markers, confined to Rab5aQ79L
vacuoles. C-terminal truncations compromise transferrin recycling and EGF/EGFR degradation.
"hRME is primarily involved in membrane trafficking through early endosomes, but not through
degradative organelles". PMID:18256511
PMID:18307993 (Girard & McPherson 2008): RME-8 depletion decreases EGFR via increased degradation;
"implicate RME-8 in sorting decisions influencing EGFR at the level of endosomes". PMID:18307993
PMID:24643499 (Freeman 2014): FAM21 (WASHC2) binds SNX1-interacting DNAJ protein RME-8. "Loss of
RME-8 causes altered kinetics of SNX1 membrane association and a pronounced increase in highly
branched endosomal tubules." Coordinates WASH complex with retromer SNX dimer membrane tubulation.
PMID:24643499

Disease

DNAJC13 variants implicated in autosomal-dominant Parkinson disease (PARK21); p.Asn855Ser
characterized as affecting endosomal membrane trafficking (transferrin accumulation in endosomal
compartments). [PMID:24218364; PMID:25393719] (UniProt DISEASE/VARIANT). Pathogenicity later
questioned (same family carried TMEM230 variants, PMID:27270108).

Localization

Early endosome / early endosome membrane / endosome membrane; peripheral membrane protein.
IDA/EXP supported (PMID:18256511, PMID:24643499). [file:human/DNAJC13/DNAJC13-uniprot.txt]
IEA SubCell terms (GO:0005769, GO:0010008, GO:0031901) redundant with experimental.
HDA proteomics: membrane, extracellular exosome, lysosomal membrane — bulk MS, non-core.
Reactome TAS: plasma membrane, secretory/azurophil granule membrane (neutrophil degranulation
pathway R-HSA-6798739/6798743) — bulk granule proteome, peripheral to core endosomal function.

GOA interaction partners (IPI GO:0005515)

PMID:28514442, PMID:33961781 WITH O15126 = SCAMP1 (also in UniProt INTERACTION block).
PMID:24643499 WITH A8K0Z3 (WASHC2C/FAM21), Q12768 (WASHC5/strumpellin/KIAA0196), Q9Y4E1 (WASHC2A/FAM21A).
These are WASH complex subunits — informative; reflects WASH-complex binding.

Curation decisions

Core MF: not captured well by GOA (only bare protein binding). True MF = Hsp70/HSC70 co-chaperone
(ATPase activator / Hsp70 binding via J domain) acting in endosomal clathrin dynamics. GOA lacks
the J-domain MF terms; propose core functions for ATPase activator activity + Hsp70 binding, plus
the well-supported BP of endosome organization / regulation of endosomal transport.
receptor-mediated endocytosis (IBA): historical name; RME-8 acts on endosomes downstream of
internalization rather than at the RME step per se. Keep as non-core (broadly correct process).

Pn Notes

(DNAJC13-pn-notes.md)

DNAJC13 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O75165
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/DNAJC13/DNAJC13-ai-review.yaml
AIGR review HTML: present - genes/human/DNAJC13/DNAJC13-ai-review.html
Gene notes: present - genes/human/DNAJC13/DNAJC13-notes.md
GOA TSV: present - genes/human/DNAJC13/DNAJC13-goa.tsv
UniProt record: present - genes/human/DNAJC13/DNAJC13-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/DNAJC13.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/DNAJC13.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: 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/core annotation action counts: ACCEPT: 12; KEEP_AS_NON_CORE: 11; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

Consistency: Partial. PN frames DNAJC13 purely as a J-domain HSP70 cochaperone (GO:0030544). The review and notes agree it is an HSC70/HSPA8 co-chaperone whose internal J domain stimulates HSC70 ATPase to drive endosomal clathrin dynamics — so the cochaperone identity is consistent — but the review's center of gravity is the endosomal sorting biology (GO:0007032 endosome organization, GO:2001135, GO:2000641, GO:0071203 WASH complex). Notably the review chose GO:0001671 (ATPase activator activity) for core_functions, NOT GO:0030544, and GOA contains neither. So the specific Hsp70-binding claim is inferred, not directly annotated.
PN story / NEW pressure: GO:0030544 is verified real. Relative to GOA (which has only bare GO:0005515 for protein binding among MF terms) this is new_to_goa, not more_specific_than_existing_goa as the PN label states. The cochaperone MF is biologically defensible (J domain + HSC70 binding, conserved from C. elegans), so GO:0030544 is a reasonable ADD — but the review's preferred GO:0001671 (ATPase activator activity) is the complementary/arguably more mechanistic MF. The distinctive endosomal-sorting biology is already well captured; no further NEW term needed.
Evidence alignment: PN carries no titles; review anchors on PMID:18256511, 18307993, 24643499 (all verified) — endosomal/WASH/SNX1, none directly demonstrating Hsp70 binding (the cochaperone MF rests on UniProt + orthology). Divergence: PN emphasizes the (inferred) Hsp70 MF; literature emphasizes endosomal function.
Verdict: Cochaperone identity consistent; GO:0030544 defensible but inferred. Recommended edits: [MAP] (minor) correct DNAJC13 projected goa_status to new_to_goa; optionally co-propagate GO:0001671 (ATPase activator activity) to match the review's core MF.

Full Consistency Review

UniProt: O75165 (RME-8) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
PN placement: 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 (group/class/branch = no_mapping)
Consistency: Partial. PN frames DNAJC13 purely as a J-domain HSP70 cochaperone (GO:0030544). The review and notes agree it is an HSC70/HSPA8 co-chaperone whose internal J domain stimulates HSC70 ATPase to drive endosomal clathrin dynamics — so the cochaperone identity is consistent — but the review's center of gravity is the endosomal sorting biology (GO:0007032 endosome organization, GO:2001135, GO:2000641, GO:0071203 WASH complex). Notably the review chose GO:0001671 (ATPase activator activity) for core_functions, NOT GO:0030544, and GOA contains neither. So the specific Hsp70-binding claim is inferred, not directly annotated.
PN story / NEW pressure: GO:0030544 is verified real. Relative to GOA (which has only bare GO:0005515 for protein binding among MF terms) this is new_to_goa, not more_specific_than_existing_goa as the PN label states. The cochaperone MF is biologically defensible (J domain + HSC70 binding, conserved from C. elegans), so GO:0030544 is a reasonable ADD — but the review's preferred GO:0001671 (ATPase activator activity) is the complementary/arguably more mechanistic MF. The distinctive endosomal-sorting biology is already well captured; no further NEW term needed.
Mapping strategy: Node mapping is acceptable for the cochaperone MF, but for DNAJC13 the propagated term arguably should pair GO:0030544 with GO:0001671 (the review's choice). The J domain is internal/non-canonical, but the cochaperone role is real, so this is not an over-reach like DNAJC11.
Evidence alignment: PN carries no titles; review anchors on PMID:18256511, 18307993, 24643499 (all verified) — endosomal/WASH/SNX1, none directly demonstrating Hsp70 binding (the cochaperone MF rests on UniProt + orthology). Divergence: PN emphasizes the (inferred) Hsp70 MF; literature emphasizes endosomal function.
Verdict: Cochaperone identity consistent; GO:0030544 defensible but inferred. Recommended edits: [MAP] (minor) correct DNAJC13 projected goa_status to new_to_goa; optionally co-propagate GO:0001671 (ATPase activator activity) to match the review's core MF.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/DNAJC13/DNAJC13-ai-review.yaml
PN workbook rows: 1

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

UniProt: O75165
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: 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.

DNAJC13

Gene Description