DNAJB11 (ERdj3, also HEDJ/ERj3p/ABBP-2) is a soluble, glycosylated, ER-lumenal HSP40/J-domain co-chaperone and the principal J-protein partner of the ER HSP70 chaperone BiP (HSPA5). Through its N-terminal J domain it binds and stimulates the ATPase activity of BiP, and through a cysteine-rich substrate-binding domain it binds unfolded and misfolded peptides directly; it recruits BiP to substrates and then dissociates as BiP engages, promoting proper folding, maturation, trafficking and ERAD-targeted degradation of secretory and membrane proteins. It is a stress (UPR)-inducible component of a large ER chaperone complex (with HSPA5, HSP90B1, HYOU1, PDIA proteins, SDF2L1, UGGT1 and others) and is required for the maturation and trafficking of polycystin-1 (PKD1). Monoallelic loss-of-function variants in DNAJB11 cause an atypical autosomal-dominant polycystic kidney disease (PKD6).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: DNAJB11/ERdj3 is an ER-resident J-protein; the ER (lumen) is its site of action. Strongly supported by experimental data and phylogeny. Reason: The ER lumen is the established compartment in which ERdj3 acts as a BiP co-chaperone; the IBA call agrees with multiple experimental annotations. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0051604 protein maturation | IBA GO_REF:0000033 | ACCEPT | Summary: ERdj3 participates in maturation of secretory/membrane proteins as a BiP co-chaperone; corroborated by IMP evidence for PKD1/polycystin-1 maturation. Reason: Protein maturation is a well-supported biological-process role of ERdj3, with direct genetic evidence (PKD1 maturation/trafficking) in addition to phylogeny. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt It is necessary for maturation and correct |
| GO:0051787 misfolded protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: ERdj3 binds unfolded/misfolded substrate proteins directly via its cysteine-rich domain. Supported by IDA and phylogeny; a core molecular function (substrate/holdase binding). Reason: Direct binding to misfolded/unfolded substrates is a defining ERdj3 molecular activity, supported experimentally (PubMed:28597544 IDA; substrate-binding mutagenesis). Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt Binds directly to both unfolded |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Automated ER-lumen localization derived from the UniProt subcellular-location annotation; this is the precise and experimentally established compartment for ERdj3. Reason: ER lumen is the correct, experimentally supported localization; the IEA call agrees with TAS/IDA evidence. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0006457 protein folding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic annotation of protein folding. ERdj3 assists BiP-mediated folding rather than autonomously catalyzing it. Reason: Protein folding is a downstream process outcome of ERdj3's BiP co-chaperone activity; the direct molecular roles are BiP ATPase stimulation and substrate binding. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt required for proper |
| GO:0005515 protein binding | IPI PMID:18923428 Regulated release of ERdj3 from unfolded proteins by BiP. | KEEP AS NON CORE | Summary: Mechanistic study of the ERdj3-BiP interaction; the WITH partner is BiP/HSPA5 (P11021). Bare protein binding is uninformative, but this records the functionally central BiP interaction. Reason: Records the core ERdj3-BiP interaction, but the bare protein binding term is uninformative per curation guidelines; the informative MF (BiP binding/ATPase stimulation) is captured by other terms. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:18923428 UniProtKB:P11021 |
| GO:0005515 protein binding | IPI PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | KEEP AS NON CORE | Summary: Interaction data including BiP/HSPA5 (P11021) and the Salmonella effector SlrP (Q8ZQQ2, xeno). Bare protein binding is uninformative. Reason: Records real interactions (the meaningful one being BiP), but bare protein binding is uninformative; the xeno SlrP interaction is not part of the core function. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20335166 UniProtKB:P11021 |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | KEEP AS NON CORE | Summary: Directed interaction network capturing ERdj3 with SIMC1 (Q8NDZ2). Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative and the partner does not define ERdj3's core BiP co-chaperone function. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:21900206 UniProtKB:Q8NDZ2 |
| GO:0005515 protein binding | IPI PMID:24189400 Perturbation of the mutated EGFR interactome identifies vuln... | KEEP AS NON CORE | Summary: Mutated-EGFR interactome study capturing ERdj3-BiP/HSPA5 (P11021). Bare protein binding is uninformative. Reason: Records the core ERdj3-BiP interaction, but bare protein binding is uninformative as a core MF. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:24189400 UniProtKB:P11021 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Human interactome community study capturing ERdj3 with BiP/HSPA5 (P11021) and SIMC1 (Q8NDZ2). Bare protein binding is uninformative. Reason: Records real interactions (including BiP) but bare protein binding is uninformative as a core MF. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:P11021 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome map capturing ERdj3 with histatin-3 (HTN3, P15516). Bare protein binding is uninformative; HTN3 is a salivary peptide and likely an incidental substrate-like interaction. Reason: Records a real high-throughput interaction but bare protein binding is uninformative and the partner does not define ERdj3's core function. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:P15516 |
| 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 ERdj3 with BiP/HSPA5 (P11021) and SIMC1 (Q8NDZ2). Bare protein binding is uninformative. Reason: Records real interactions (including the core BiP partner) but bare protein binding is uninformative as a core MF. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:P11021 |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog-projected molecular function. There is no direct evidence that the ER-lumenal ERdj3 acts as a signaling receptor ligand; this conflicts with its established BiP co-chaperone function. Reason: Orthology-projected term unsupported for human ERdj3 and inconsistent with its ER-lumenal chaperone role; likely an over-annotation. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005102 signaling receptor binding molecular_function ECO:0000265 IEA GO_REF:0000107 |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog-projected extracellular localization. ERdj3 is an ER-lumenal resident; although a minor secreted pool has been described for ERdj3, this orthology transfer conflicts with the predominant, functionally relevant ER-lumen localization. Reason: Orthology-projected extracellular localization is not the functionally relevant compartment for ERdj3 and conflicts with its established ER-lumen residence. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005576 extracellular region cellular_component ECO:0000265 IEA GO_REF:0000107 |
| GO:0005634 nucleus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog-projected nuclear localization. UniProt explicitly cautions that a reported nuclear/cytosolic localization arose from an N-terminal GFP tag disrupting signal-peptide-driven ER targeting and is not the in vivo localization. Reason: Nuclear localization is an artifact of tag-disrupted ER targeting per UniProt CAUTION; ERdj3 is an ER-lumenal protein, so this is an over-annotation. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt reported a cytosolic, as well as nuclear |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog-projected cytoplasmic localization, also attributable to the tag-disrupted-targeting artifact described by UniProt. ERdj3 is ER-lumenal. Reason: Cytoplasmic localization conflicts with signal-peptide-driven ER-lumen targeting and reflects an over-annotation/artifact, not the in vivo localization. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt reported a cytosolic, as well as nuclear |
| GO:0034663 endoplasmic reticulum chaperone complex | IEA GO_REF:0000107 | ACCEPT | Summary: ERdj3 is a component of a large ER chaperone complex (with HSPA5, HSP90B1, HYOU1, PDIA proteins, SDF2L1, UGGT1, etc.). The orthology-projected term agrees with experimentally documented complex membership. Reason: ERdj3's membership in the ER chaperone complex is experimentally established (UniProt SUBUNIT; PubMed:12475965), so this localization is correct. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt Part of a large chaperone multiprotein complex |
| GO:0044183 protein folding chaperone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-projected general chaperone molecular function. ERdj3 is a J-protein co-chaperone that binds substrates and assists BiP; the term is broadly consistent though less specific than its BiP co-chaperone/substrate-binding activities. Reason: A correct but general chaperone term; the more informative core functions (BiP ATPase stimulation, misfolded protein binding) are captured by specific terms. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt ER-associated Hsp40 co-chaperone |
| GO:0140309 unfolded protein holdase activity | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-projected holdase activity. ERdj3 binds unfolded substrates ATP-independently and holds them prior to BiP engagement, consistent with holdase activity. Reason: ERdj3's documented ATP-independent binding of denatured substrates supports an unfolded-protein holdase activity. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt Binds to denatured substrates in an ATP-independent manner |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct (HPA immunofluorescence) evidence for ER localization, consistent with ERdj3's ER-lumenal residence. Reason: IDA ER localization corroborates the established ER-lumen site of action. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA GO_REF:0000052 |
| GO:0051787 misfolded protein binding | IDA PMID:28597544 Endoplasmic reticulum proteins SDF2 and SDF2L1 act as compon... | ACCEPT | Summary: Direct evidence that ERdj3 binds misfolded proteins, part of the BiP chaperone cycle preventing protein aggregation. A core molecular function. Reason: Direct experimental evidence for misfolded-protein binding underpins ERdj3's substrate-recognition role. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt Binds directly to both unfolded |
| GO:0101031 protein folding chaperone complex | IPI PMID:28597544 Endoplasmic reticulum proteins SDF2 and SDF2L1 act as compon... | ACCEPT | Summary: ERdj3 is part of a chaperone complex with SDF2/SDF2L1 (Q99470/Q9HCN8) in the BiP chaperone cycle. Consistent with its membership in the ER chaperone machinery. Reason: Experimentally supported membership in a BiP-cycle chaperone complex, consistent with the ER chaperone complex annotation. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0101031 protein folding chaperone complex cellular_component ECO:0000353 IPI PMID:28597544 |
| GO:0051604 protein maturation | IMP PMID:29706351 Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Do... | ACCEPT | Summary: DNAJB11-null cells and patient tissue show maturation and trafficking defects of polycystin-1 (PC1/PKD1) and other secretory proteins, demonstrating ERdj3's role in protein maturation. This is the disease-relevant core process. Reason: Direct genetic/mutant-phenotype (IMP) evidence that ERdj3 is required for maturation/trafficking of client proteins (PKD1), underlying PKD6 pathogenesis. Supporting Evidence: PMID:29706351 maturation and trafficking defects involving the ADPKD protein |
| GO:0005783 endoplasmic reticulum | IDA PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | ACCEPT | Summary: Direct evidence for ER localization, consistent with ERdj3's ER-lumenal residence. Reason: IDA ER localization corroborates the established ER site of action. Supporting Evidence: file:human/DNAJB11/DNAJB11-goa.tsv GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA PMID:20335166 |
| GO:0032781 positive regulation of ATP-dependent activity | IDA PMID:20335166 The Salmonella type III secretion effector, salmonella leuci... | ACCEPT | Summary: Direct evidence that ERdj3 positively regulates an ATP-dependent activity, reflecting stimulation of BiP/HSPA5 ATPase activity by the J domain. This is a core molecular activity of ERdj3. Reason: ERdj3's J domain stimulates BiP ATPase activity (UniProt FUNCTION; PubMed:18923428), and this IDA captures that activation; central to its co-chaperone role. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt Stimulates HSPA5 ATPase activity |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: High-throughput membrane-proteome (NK cell) detection. ERdj3 is a soluble ER-lumenal protein; UniProt notes ER-membrane association only with a C-terminally tagged construct. This generic membrane localization is non-core. Reason: ERdj3 is soluble in the ER lumen; the generic membrane assignment from a proteomics screen is peripheral and not its functional compartment. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt Associated with the ER membrane in a C-terminally epitope-tagged construct |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-1791075 | ACCEPT | Summary: Reactome-curated ER-lumen localization, consistent with the precise, experimentally established compartment. Reason: ER lumen is the correct, well-supported localization for ERdj3. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005783 endoplasmic reticulum | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | ACCEPT | Summary: Author-stated ER localization, consistent with ERdj3's ER residence. Reason: TAS ER localization agrees with the established ER-lumen site of action. Supporting Evidence: file:human/DNAJB11/DNAJB11-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
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Download this section (compressed HTML)Q: Which secretory/membrane clients besides PKD1 and UMOD depend on ERdj3 for ER maturation, and how does the cysteine-rich substrate-binding domain define client specificity?
Q: How do PKD6-causing DNAJB11 variants mechanistically impair BiP co-chaperone activity (substrate binding vs. BiP ATPase stimulation), and does haploinsufficiency versus dominant-negative action explain the phenotype?
Experiment: Reconstituted assays measuring ERdj3-stimulated BiP ATPase activity and substrate holdase binding for wild-type versus PKD6 variants (P54R, L77P, truncation).
Experiment: Proximity-labeling or client-capture proteomics in DNAJB11-null versus wild-type cells to define the ERdj3-dependent secretory clientome and quantify PC1/UMOD maturation.
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