DNAJB11

UniProt ID: Q9UBS4
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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).

Existing Annotations Review

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

Core Functions

ER-lumenal J-domain co-chaperone of BiP (HSPA5) that stimulates BiP's ATPase activity via its J domain, coupling substrate delivery to BiP's ATP-dependent folding cycle.

Molecular Function:
ATPase activator activity
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • file:human/DNAJB11/DNAJB11-uniprot.txt
    Stimulates HSPA5 ATPase activity
  • PMID:18923428
    the ability to stimulate BiP's ATPase

Binds unfolded and misfolded substrate proteins directly (ATP-independent holdase via its cysteine-rich domain), recruiting BiP to nascent and ERAD substrates to promote folding, maturation, trafficking and degradation in the ER.

Molecular Function:
misfolded protein binding
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • file:human/DNAJB11/DNAJB11-uniprot.txt
    Binds directly to both unfolded
  • file:human/DNAJB11/DNAJB11-uniprot.txt
    Binds to denatured substrates in an ATP-independent manner

Required for the maturation and correct trafficking of secretory/membrane clients including polycystin-1 (PKD1); loss causes ADPKD (PKD6).

Molecular Function:
ATPase activator activity
Directly Involved In:
protein maturation
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • file:human/DNAJB11/DNAJB11-uniprot.txt
    It is necessary for maturation and correct
  • PMID:29706351
    maturation and trafficking defects involving the ADPKD protein

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
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
PMID:16130169
Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
PMID:18923428
Regulated release of ERdj3 from unfolded proteins by BiP.
  • ERdj3 binds unfolded substrates and recruits BiP; BiP releases ERdj3 from substrate only in the presence of ATP and requires ERdj3 stimulation of BiP's ATPase activity.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20335166
The Salmonella type III secretion effector, salmonella leucine-rich repeat protein (SlrP), targets the human chaperone ERdj3.
  • ERdj3 localizes to the ER and positively regulates an ATP-dependent activity (stimulation of BiP ATPase); the Salmonella effector SlrP targets ERdj3.
PMID:21900206
A directed protein interaction network for investigating intracellular signal transduction.
PMID:24189400
Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:28597544
Endoplasmic reticulum proteins SDF2 and SDF2L1 act as components of the BiP chaperone cycle to prevent protein aggregation.
  • ERdj3 binds misfolded proteins and is part of a BiP chaperone-cycle complex (with SDF2/SDF2L1) that prevents protein aggregation in the ER.
PMID:29706351
Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.
  • DNAJB11 is a co-factor of BiP, and DNAJB11-null cells/patient tissue show maturation and trafficking defects of the ADPKD protein PC1 (PKD1) and other secretory proteins.
  • Monoallelic loss-of-function DNAJB11 variants cause an atypical autosomal-dominant polycystic kidney disease that is a phenotypic hybrid of ADPKD and ADTKD.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Reactome:R-HSA-1791075
Reactome pathway annotation (ER lumen localization of DNAJB11/ERdj3)

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(DNAJB11-notes.md)

DNAJB11 (ERdj3 / HEDJ / ERj3p) research notes

UniProt: Q9UBS4. 358 aa, precursor (signal 1-22), J-domain 25-90. ER-lumenal HSP40/J-protein.
Soluble, glycosylated (N-261), disulfide-bonded Cys-rich domain. Paralog within DNAJB but ER-resident.

Core function: BiP (HSPA5) co-chaperone in ER lumen

  • [UniProt FUNCTION "As a co-chaperone for HSPA5 it is required for proper folding, trafficking or
    degradation of proteins... Binds directly to both unfolded proteins that are substrates for ERAD and
    nascent unfolded peptide chains... Stimulates HSPA5 ATPase activity... necessary for maturation and
    correct trafficking of PKD1."]
  • PMID:18923428. ERdj3 binds substrate first, recruits BiP,
    stimulates BiP ATPase.
  • GOA: GO:0032781 positive regulation of ATP-dependent activity IDA PMID:20335166 (= stimulates BiP
    ATPase). GO:0051787 misfolded protein binding IDA PMID:28597544 + IBA. GO:0051604 protein maturation
    IMP PMID:29706351 + IBA.

Substrate binding domain

  • Binds denatured substrates ATP-independently via Cys-rich domain (Cys169/171/193/196 mutations
    abolish substrate binding, PMID:17976514). H53Q (J-domain HPD) abolishes BiP binding but not
    substrate binding (PMID:15525676).

ER chaperone complex

  • Part of large ER chaperone complex: DNAJB11, HSP90B1, HSPA5, HYOU1, PDIA2/4/6, PPIB, SDF2L1, UGGT1
    (UniProt SUBUNIT; PMID:12475965). GOA part_of GO:0101031 protein folding chaperone complex IPI
    PMID:28597544 (with SDF2/SDF2L1 Q99470/Q9HCN8). GO:0034663 ER chaperone complex IEA.

Disease: ADPKD (PKD6)

Localization — ER lumen (core). Conflicting IEA over-annotations to flag:

  • ER lumen/ER: well established (UniProt, IDA HPA, TAS Reactome). CORE.
  • Ensembl ortholog-projected (GO_REF:0000107) extracellular (GO:0005576), nucleus (GO:0005634),
    cytoplasm (GO:0005737), signaling receptor binding (GO:0005102) — these CONFLICT with the
    signal-peptide-driven ER-lumen targeting. UniProt CAUTION: cytosolic/nuclear localization was an
    artifact of N-terminal GFP tag disrupting signal peptide; APOBEC1/PWP1 interactions dubious.
    => MARK_AS_OVER_ANNOTATED for extracellular/nucleus/cytoplasm/signaling-receptor-binding.
  • GO:0016020 membrane HDA PMID:19946888 (NK membrane proteome) — UniProt notes ER-membrane
    association only with C-terminally tagged construct; ERdj3 is a soluble ER-lumen protein. KEEP_AS_NON_CORE.

Protein-binding IPIs

  • HSPA5/BiP (P11021): the functionally meaningful one (PMID:18923428, 24189400, 28514442, 33961781,
    20335166). KEEP_AS_NON_CORE bare protein binding but reflects core BiP interaction.
  • SIMC1 (Q8NDZ2), HTN3 (P15516 histatin-3), SlrP (Q8ZQQ2 Salmonella, xeno): HT/substrate. NON_CORE.

MF assignment

  • Core MF: GO:0001671 ATPase activator activity (stimulates BiP ATPase) — UniProt-supported.
  • Core MF: GO:0051787 misfolded protein binding (IDA) / GO:0051082 unfolded protein binding (IBA) /
    GO:0140309 unfolded protein holdase activity — substrate (holdase) binding.
  • GO:0006457 protein folding, GO:0051604 protein maturation: downstream BP, core process for ERdj3
    given disease relevance (protein maturation IMP is genuine). Keep protein maturation as ACCEPT/core process.

Pn Notes

(DNAJB11-pn-notes.md)

DNAJB11 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9UBS4
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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).
  • Existing/core annotation action counts: ACCEPT: 14; KEEP_AS_NON_CORE: 10; MARK_AS_OVER_ANNOTATED: 4

PN Consistency Summary

  • Consistency: Strong agreement on the core. Notes/YAML describe a soluble ER-lumenal BiP (HSPA5) co-chaperone that stimulates BiP ATPase (GO:0032781 IDA PMID:20335166) and binds misfolded substrates directly via a Cys-rich domain (GO:0051787 IDA PMID:28597544; GO:0140309 holdase IEA). The PN HSP70-cochaperone type fits BiP partnership. One subtlety: the PN type uses GO:0030544 "Hsp70 protein binding," but DNAJB11's partner is the ER HSP70 BiP — biologically Hsp70-family, so consistent. The row2 "secreted during ER stress" PN note aligns with the minor secreted pool the review flags but downgrades; review marks orthology-projected extracellular (GO:0005576) as over-annotated for the core compartment — a defensible nuance, not a contradiction.
  • PN story / NEW pressure: PN's HSP70-binding assertion is captured (GO:0051787 misfolded protein binding ACCEPT/core; GO:0140309 holdase ACCEPT; core_functions also assert GO:0001671 ATPase activator). Genuine direct-substrate/holdase MF distinguishes ERdj3 from members lacking such data. PN-projected GO:0030544 (verified real) is narrower than the BiP-binding evidence; already captured. No NEW-term pressure (disease/PKD1 maturation = GO:0051604 IMP, captured).
  • Evidence alignment: Review's BiP-mechanism PMIDs (18923428, 20335166, 28597544) and disease PMID:29706351 are the substantive set; PN supplies path/title-level context only. No conflict.
  • Verdict: CONSISTENT — strong direct evidence; GO:0030544 a sound narrower specialization of the verified BiP-cochaperone/holdase MF.

Full Consistency Review

  • UniProt: Q9UBS4 (ERdj3/HEDJ) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: row1 ER proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone (mapped→GO:0030544); row2 Extracellular proteostasis|Chaperone|Primarily intracellular, secreted during ER stress (no_mapping) (branches ER, EX)
  • Consistency: Strong agreement on the core. Notes/YAML describe a soluble ER-lumenal BiP (HSPA5) co-chaperone that stimulates BiP ATPase (GO:0032781 IDA PMID:20335166) and binds misfolded substrates directly via a Cys-rich domain (GO:0051787 IDA PMID:28597544; GO:0140309 holdase IEA). The PN HSP70-cochaperone type fits BiP partnership. One subtlety: the PN type uses GO:0030544 "Hsp70 protein binding," but DNAJB11's partner is the ER HSP70 BiP — biologically Hsp70-family, so consistent. The row2 "secreted during ER stress" PN note aligns with the minor secreted pool the review flags but downgrades; review marks orthology-projected extracellular (GO:0005576) as over-annotated for the core compartment — a defensible nuance, not a contradiction.
  • PN story / NEW pressure: PN's HSP70-binding assertion is captured (GO:0051787 misfolded protein binding ACCEPT/core; GO:0140309 holdase ACCEPT; core_functions also assert GO:0001671 ATPase activator). Genuine direct-substrate/holdase MF distinguishes ERdj3 from members lacking such data. PN-projected GO:0030544 (verified real) is narrower than the BiP-binding evidence; already captured. No NEW-term pressure (disease/PKD1 maturation = GO:0051604 IMP, captured).
  • Mapping strategy: GO:0030544 mapping is defensible; ERdj3 has direct BiP-interaction and ATPase-stimulation evidence, so the type-level mapping does NOT over-reach. Row2 extracellular no_mapping is correct.
  • Evidence alignment: Review's BiP-mechanism PMIDs (18923428, 20335166, 28597544) and disease PMID:29706351 are the substantive set; PN supplies path/title-level context only. No conflict.
  • Verdict: CONSISTENT — strong direct evidence; GO:0030544 a sound narrower specialization of the verified BiP-cochaperone/holdase MF.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJB11/DNAJB11-ai-review.yaml
  • PN workbook rows: 2

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

  • UniProt: Q9UBS4
  • In branches: ER, EX
  • PN-node mapping records (path + ancestors):
    • [type] ER 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] ER proteostasis|Chaperone|HSP70 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [class] ER proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER 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.

PN row 2: Extracellular proteostasis | Chaperone | Primarily intracellular, secreted during ER stress

  • UniProt: Q9UBS4
  • In branches: ER, EX
  • PN-node mapping records (path + ancestors):
    • [group] Extracellular proteostasis|Chaperone|Primarily intracellular, secreted during ER stress
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN bucket. The label is useful for curator triage, but no direct GO mapping is appropriate because propagation would add a process, activity, or localization not shared cleanly by all members.
    • [class] Extracellular 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] Extracellular 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=ER 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: Q9UBS4
gene_symbol: DNAJB11
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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).
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: DNAJB11/ERdj3 is an ER-resident J-protein; the ER (lumen) is its site of action. Strongly supported by experimental data and phylogeny.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ERdj3 participates in maturation of secretory/membrane proteins as a BiP co-chaperone; corroborated by IMP evidence for PKD1/polycystin-1 maturation.
    action: ACCEPT
    reason: Protein maturation is a well-supported biological-process role of ERdj3, with direct genetic evidence (PKD1 maturation/trafficking) in addition to phylogeny.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: It is necessary for maturation and correct
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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).
    action: ACCEPT
    reason: Direct binding to misfolded/unfolded substrates is a defining ERdj3 molecular activity, supported experimentally (PubMed:28597544 IDA; substrate-binding mutagenesis).
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: Binds directly to both unfolded
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated ER-lumen localization derived from the UniProt subcellular-location annotation; this is the precise and experimentally established compartment for ERdj3.
    action: ACCEPT
    reason: ER lumen is the correct, experimentally supported localization; the IEA call agrees with TAS/IDA evidence.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic annotation of protein folding. ERdj3 assists BiP-mediated folding rather than autonomously catalyzing it.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: required for proper
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18923428
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:18923428 UniProtKB:P11021
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20335166
  qualifier: enables
  review:
    summary: Interaction data including BiP/HSPA5 (P11021) and the Salmonella effector SlrP (Q8ZQQ2, xeno). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20335166 UniProtKB:P11021
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21900206
  qualifier: enables
  review:
    summary: Directed interaction network capturing ERdj3 with SIMC1 (Q8NDZ2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative and the partner does not define ERdj3's core BiP co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:21900206 UniProtKB:Q8NDZ2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24189400
  qualifier: enables
  review:
    summary: Mutated-EGFR interactome study capturing ERdj3-BiP/HSPA5 (P11021). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the core ERdj3-BiP interaction, but bare protein binding is uninformative as a core MF.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:24189400 UniProtKB:P11021
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Human interactome community study capturing ERdj3 with BiP/HSPA5 (P11021) and SIMC1 (Q8NDZ2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions (including BiP) but bare protein binding is uninformative as a core MF.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:P11021
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Records a real high-throughput interaction but bare protein binding is uninformative and the partner does not define ERdj3's core function.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:P15516
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing ERdj3 with BiP/HSPA5 (P11021) and SIMC1 (Q8NDZ2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions (including the core BiP partner) but bare protein binding is uninformative as a core MF.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:P11021
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Orthology-projected term unsupported for human ERdj3 and inconsistent with its ER-lumenal chaperone role; likely an over-annotation.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005102 signaling receptor binding molecular_function ECO:0000265 IEA GO_REF:0000107
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Orthology-projected extracellular localization is not the functionally relevant compartment for ERdj3 and conflicts with its established ER-lumen residence.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005576 extracellular region cellular_component ECO:0000265 IEA GO_REF:0000107
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: reported a cytosolic, as well as nuclear
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl ortholog-projected cytoplasmic localization, also attributable to the tag-disrupted-targeting artifact described by UniProt. ERdj3 is ER-lumenal.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cytoplasmic localization conflicts with signal-peptide-driven ER-lumen targeting and reflects an over-annotation/artifact, not the in vivo localization.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: reported a cytosolic, as well as nuclear
- term:
    id: GO:0034663
    label: endoplasmic reticulum chaperone complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    reason: ERdj3's membership in the ER chaperone complex is experimentally established (UniProt SUBUNIT; PubMed:12475965), so this localization is correct.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: Part of a large chaperone multiprotein complex
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: A correct but general chaperone term; the more informative core functions (BiP ATPase stimulation, misfolded protein binding) are captured by specific terms.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: ER-associated Hsp40 co-chaperone
- term:
    id: GO:0140309
    label: unfolded protein holdase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Orthology-projected holdase activity. ERdj3 binds unfolded substrates ATP-independently and holds them prior to BiP engagement, consistent with holdase activity.
    action: ACCEPT
    reason: ERdj3's documented ATP-independent binding of denatured substrates supports an unfolded-protein holdase activity.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: Binds to denatured substrates in an ATP-independent manner
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (HPA immunofluorescence) evidence for ER localization, consistent with ERdj3's ER-lumenal residence.
    action: ACCEPT
    reason: IDA ER localization corroborates the established ER-lumen site of action.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA GO_REF:0000052
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:28597544
  qualifier: enables
  review:
    summary: Direct evidence that ERdj3 binds misfolded proteins, part of the BiP chaperone cycle preventing protein aggregation. A core molecular function.
    action: ACCEPT
    reason: Direct experimental evidence for misfolded-protein binding underpins ERdj3's substrate-recognition role.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: Binds directly to both unfolded
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IPI
  original_reference_id: PMID:28597544
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    reason: Experimentally supported membership in a BiP-cycle chaperone complex, consistent with the ER chaperone complex annotation.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0101031 protein folding chaperone complex cellular_component ECO:0000353 IPI PMID:28597544
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IMP
  original_reference_id: PMID:29706351
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Direct genetic/mutant-phenotype (IMP) evidence that ERdj3 is required for maturation/trafficking of client proteins (PKD1), underlying PKD6 pathogenesis.
    supported_by:
    - reference_id: PMID:29706351
      supporting_text: maturation and trafficking defects involving the ADPKD protein
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:20335166
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization, consistent with ERdj3's ER-lumenal residence.
    action: ACCEPT
    reason: IDA ER localization corroborates the established ER site of action.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-goa.tsv
      supporting_text: GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA PMID:20335166
- term:
    id: GO:0032781
    label: positive regulation of ATP-dependent activity
  evidence_type: IDA
  original_reference_id: PMID:20335166
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: Stimulates HSPA5 ATPase activity
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_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.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: Associated with the ER membrane in a C-terminally epitope-tagged construct
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1791075
  qualifier: located_in
  review:
    summary: Reactome-curated ER-lumen localization, consistent with the precise, experimentally established compartment.
    action: ACCEPT
    reason: ER lumen is the correct, well-supported localization for ERdj3.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:16130169
  qualifier: located_in
  review:
    summary: Author-stated ER localization, consistent with ERdj3's ER residence.
    action: ACCEPT
    reason: TAS ER localization agrees with the established ER-lumen site of action.
    supported_by:
    - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
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: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
  findings: []
- id: PMID:18923428
  title: Regulated release of ERdj3 from unfolded proteins by BiP.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches; Results show ERdj3 binds unfolded substrates and stimulates BiP ATPase, supporting DNAJB11's core ER co-chaperone/Hsp70-recruitment function.
  findings:
  - statement: ERdj3 binds unfolded substrates and recruits BiP; BiP releases ERdj3 from substrate only in the presence of ATP and requires ERdj3 stimulation of BiP's ATPase activity.
    reference_section_type: RESULTS
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20335166
  title: The Salmonella type III secretion effector, salmonella leucine-rich repeat protein (SlrP), targets the human chaperone ERdj3.
  findings:
  - statement: ERdj3 localizes to the ER and positively regulates an ATP-dependent activity (stimulation of BiP ATPase); the Salmonella effector SlrP targets ERdj3.
    reference_section_type: RESULTS
- id: PMID:21900206
  title: A directed protein interaction network for investigating intracellular signal transduction.
  findings: []
- id: PMID:24189400
  title: Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:28597544
  title: Endoplasmic reticulum proteins SDF2 and SDF2L1 act as components of the BiP chaperone cycle to prevent protein aggregation.
  findings:
  - statement: ERdj3 binds misfolded proteins and is part of a BiP chaperone-cycle complex (with SDF2/SDF2L1) that prevents protein aggregation in the ER.
    reference_section_type: RESULTS
- id: PMID:29706351
  title: Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; body confirms DNAJB11 is
      a BiP co-factor whose monoallelic loss-of-function causes atypical ADPKD with
      PC1/PKD1 maturation and trafficking defects, supporting the gene's in-vivo ER
      co-chaperone function.
  findings:
  - statement: DNAJB11 is a co-factor of BiP, and DNAJB11-null cells/patient tissue show maturation and trafficking defects of the ADPKD protein PC1 (PKD1) and other secretory proteins.
    reference_section_type: RESULTS
  - statement: Monoallelic loss-of-function DNAJB11 variants cause an atypical autosomal-dominant polycystic kidney disease that is a phenotypic hybrid of ADPKD and ADTKD.
    reference_section_type: RESULTS
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: Reactome:R-HSA-1791075
  title: Reactome pathway annotation (ER lumen localization of DNAJB11/ERdj3)
  findings: []
core_functions:
- description: ER-lumenal J-domain co-chaperone of BiP (HSPA5) that stimulates BiP's ATPase activity via its J domain, coupling substrate delivery to BiP's ATP-dependent folding cycle.
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
    supporting_text: Stimulates HSPA5 ATPase activity
  - reference_id: PMID:18923428
    supporting_text: the ability to stimulate BiP's ATPase
- description: Binds unfolded and misfolded substrate proteins directly (ATP-independent holdase via its cysteine-rich domain), recruiting BiP to nascent and ERAD substrates to promote folding, maturation, trafficking and degradation in the ER.
  molecular_function:
    id: GO:0051787
    label: misfolded protein binding
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
    supporting_text: Binds directly to both unfolded
  - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
    supporting_text: Binds to denatured substrates in an ATP-independent manner
- description: Required for the maturation and correct trafficking of secretory/membrane clients including polycystin-1 (PKD1); loss causes ADPKD (PKD6).
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/DNAJB11/DNAJB11-uniprot.txt
    supporting_text: It is necessary for maturation and correct
  - reference_id: PMID:29706351
    supporting_text: maturation and trafficking defects involving the ADPKD protein
  directly_involved_in:
  - id: GO:0051604
    label: protein maturation
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
suggested_experiments:
- description: Reconstituted assays measuring ERdj3-stimulated BiP ATPase activity and substrate holdase binding for wild-type versus PKD6 variants (P54R, L77P, truncation).
- description: 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.