id: Q9UGP8
gene_symbol: SEC63
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SEC63 (also DNAJC23) is a multi-pass endoplasmic reticulum membrane protein and an auxiliary component of the Sec61 translocon. It contains a luminal J-domain (DnaJ/Hsp40-type) and two Sec63 domains. Together with SEC62 it forms the SEC62-SEC63 subcomplex that supports cotranslational and post-translational translocation of precursor polypeptides into the ER. Its defining mechanism is co-chaperone activity, in which the luminal J-domain recruits and stimulates the ATPase cycle of the ER Hsp70 chaperone BiP (HSPA5), positioning BiP on incoming polypeptides at the translocon to drive and gate their translocation into the ER lumen. SEC63 cooperates with SEC62 and BiP in importing small presecretory proteins with short, apolar signal peptides, and is required for efficient biogenesis and trafficking of polycystin-1 (PKD1). SEC63 is widely expressed with high levels in liver, and loss-of-function variants cause autosomal dominant polycystic liver disease (PCLD2).
existing_annotations:
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: RNA binding is not an established core function of SEC63, an ER-membrane translocon J-domain co-chaperone. This phylogenetic (IBA) annotation appears propagated from high-throughput mRNA-interactome captures rather than a demonstrated, conserved sequence-specific RNA-binding activity; the J-domain and Sec63 domains are not canonical RNA-binding modules.
    action: KEEP_AS_NON_CORE
    reason: RNA binding is not a demonstrated core function of SEC63; the IBA propagation likely derives from incidental mRNA-interactome captures (consistent with translocon proximity to translating ribosomes/mRNA) rather than a sequence-specific RNA-binding activity, so it is retained but marked non-core.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER)
- term:
    id: GO:0006614
    label: SRP-dependent cotranslational protein targeting to membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SEC63 participates in cotranslational translocation of precursors into the ER as a translocon-associated co-chaperone, consistent with the conserved family role.
    action: ACCEPT
    reason: Core biological process; SEC63 supports cotranslational transport of precursor polypeptides across the ER membrane.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER)
- term:
    id: GO:0006620
    label: post-translational protein targeting to endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SEC63 mediates post-translational targeting/translocation of precursors to the ER membrane; conserved across the family.
    action: ACCEPT
    reason: Core biological process; SEC63 (with SEC62 and BiP) supports post-translational ER import.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER)
- term:
    id: GO:0031207
    label: Sec62/Sec63 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: SEC63 is a defining subunit of the SEC62-SEC63 subcomplex of the ER translocon, conserved across the family.
    action: ACCEPT
    reason: Core cellular component; SEC63 forms the Sec62/Sec63 complex with SEC62.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: different auxiliary components such as SEC62 and SEC63
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SEC63 is a multi-pass ER membrane protein; ER membrane is its core localization.
    action: ACCEPT
    reason: Core cellular component; UniProt records SEC63 as an ER-membrane multi-pass protein.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass'
- term:
    id: GO:0006614
    label: SRP-dependent cotranslational protein targeting to membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic assignment of cotranslational ER targeting, consistent with the IBA/IMP evidence.
    action: ACCEPT
    reason: Correct core biological process; redundant with experimental and phylogenetic evidence.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER)
- term:
    id: GO:0006620
    label: post-translational protein targeting to endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic assignment of post-translational ER targeting, consistent with IBA/IMP evidence.
    action: ACCEPT
    reason: Correct core biological process; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21251912
  qualifier: enables
  review:
    summary: SEC63 interacts with cytosolic nucleoredoxin (NRX), an interaction proposed to link SEC63 to Wnt signaling and to polycystic liver disease. A genuine and disease-relevant interaction, but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real SEC63-nucleoredoxin interaction (disease-relevant) but bare protein binding is uninformative and not the core translocon co-chaperone function.
    supported_by:
    - reference_id: PMID:21251912
      supporting_text: we identified the cytosolic protein nucleoredoxin (NRX) as an interaction partner of human Sec63
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: Alternative-splicing interactome screen capture; bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome interaction; uninformative bare term not elevated to core.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: 'Q9UGP8; Q6FHY5: MEOX2'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with SEC63's translocon-associated function.
    action: ACCEPT
    reason: Correct compartment; the more specific ER membrane localization is also annotated.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0031204
    label: post-translational protein targeting to membrane, translocation
  evidence_type: IMP
  original_reference_id: PMID:29719251
  qualifier: involved_in
  review:
    summary: SEC63, with BiP, acts as an auxiliary translocation component during chaperone-mediated Sec61 channel gating for import of small precursors; the J-domain (H132/HPD) mutant reduces translocation.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support; SEC63 supports translocation of precursors across the ER membrane.
    supported_by:
    - reference_id: PMID:29719251
      supporting_text: Sec63 and the lumenal chaperone BiP act as auxiliary translocation components
    - reference_id: PMID:32133789
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: SEC63 was captured in a high-throughput mRNA-interactome (RNA-binding proteome) screen. This is real data but does not establish a physiological RNA-binding function for an ER-membrane translocon co-chaperone.
    action: KEEP_AS_NON_CORE
    reason: High-throughput proteome-wide RNA-interactome capture; not a demonstrated core function of SEC63 and likely reflects proximity to translating ribosomes/mRNA at the translocon rather than direct sequence-specific RNA binding.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: 'F:RNA binding; HDA:UniProtKB'
- term:
    id: GO:0006614
    label: SRP-dependent cotranslational protein targeting to membrane
  evidence_type: IMP
  original_reference_id: PMID:22375059
  qualifier: acts_upstream_of_or_within
  review:
    summary: Depletion studies of Sec61/Sec62/Sec63 demonstrate SEC63's role in cotranslational transport of polypeptides into the ER.
    action: ACCEPT
    reason: Core biological process with experimental (IMP) support.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER)
- term:
    id: GO:0006620
    label: post-translational protein targeting to endoplasmic reticulum membrane
  evidence_type: IMP
  original_reference_id: PMID:22375059
  qualifier: acts_upstream_of_or_within
  review:
    summary: Depletion studies demonstrate SEC63's role in post-translational targeting of precursors to the ER membrane.
    action: ACCEPT
    reason: Core biological process with experimental (IMP) support.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER)
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:22375059
  qualifier: located_in
  review:
    summary: SEC63 is a membrane protein; "membrane" is a correct but generic parent of the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; ER membrane (GO:0005789) is the more specific and informative localization.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: Multi-pass
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:10799540
  qualifier: located_in
  review:
    summary: SEC63 is an ER protein associated with the Sec61 translocon; ER localization is correct.
    action: ACCEPT
    reason: Correct compartment; redundant with the more specific ER membrane annotations.
    supported_by:
    - reference_id: PMID:10799540
      supporting_text: a membrane protein complex that consists of the Sec61p complex and the Sec62p-Sec63p subcomplex
- term:
    id: GO:0006612
    label: protein targeting to membrane
  evidence_type: TAS
  original_reference_id: PMID:10799540
  qualifier: involved_in
  review:
    summary: SEC63 is involved in targeting/translocation of proteins to the ER membrane; protein targeting to membrane is a correct but generic parent of the specific ER translocation terms.
    action: ACCEPT
    reason: Correct general biological process; the specific post-translational/cotranslational ER targeting terms better capture SEC63's role.
    supported_by:
    - reference_id: PMID:10799540
      supporting_text: a membrane protein complex that consists of the Sec61p
- term:
    id: GO:0038023
    label: signaling receptor activity
  evidence_type: TAS
  original_reference_id: PMID:10799540
  qualifier: enables
  review:
    summary: SEC63 is a translocon-associated J-domain co-chaperone that recruits/stimulates BiP, not a signal-transduction (signaling) receptor. The signaling receptor activity term mischaracterizes its molecular function; this is a legacy ProtInc annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: SEC63 functions as a DnaJ-type co-chaperone at the Sec61 translocon, not a signal-transduction receptor; signaling receptor activity over-extends/misframes its molecular function.
    supported_by:
    - reference_id: file:human/SEC63/SEC63-uniprot.txt
      supporting_text: a membrane protein complex that consists of the Sec61p complex and the Sec62p-Sec63p subcomplex
references:
- 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, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10799540
  title: Mammalian Sec61 is associated with Sec62 and Sec63.
  findings:
  - statement: Post-translational ER transport is mediated by a membrane protein complex consisting of the Sec61 complex and the Sec62-Sec63 subcomplex; establishes mammalian SEC63 association with the Sec61 translocon.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the Sec61-Sec62-Sec63 association in mammalian cells; source of ER localization and protein-targeting-to-membrane annotations (and the misframed signaling-receptor TAS).
- id: PMID:21251912
  title: An interaction between human Sec63 and nucleoredoxin may provide the missing
    link between the SEC63 gene and polycystic liver disease.
  findings:
  - statement: Yeast two-hybrid identification of nucleoredoxin (NRX) as a SEC63 interaction partner, linking SEC63 to Wnt signaling and proposing a mechanism for SEC63-related polycystic liver disease.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the SEC63-nucleoredoxin protein-binding annotation; disease-relevant but uninformative as a bare protein binding term.
- id: PMID:22375059
  title: Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides
    into the endoplasmic reticulum of mammalian cells.
  findings:
  - statement: Depletion of Sec61alpha, Sec62 and Sec63 has different effects on cotranslational and post-translational ER transport; establishes SEC63 as an ER-membrane translocation component.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct functional study of SEC63 in ER protein transport; source of ER-membrane localization and ER targeting/translocation annotations.
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-wide mRNA-interactome atlas; source of the HDA RNA-binding capture, not a demonstrated physiological RNA-binding function for SEC63.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
- id: PMID:29719251
  title: Chaperone-Mediated Sec61 Channel Gating during ER Import of Small Precursor
    Proteins Overcomes Sec61 Inhibitor-Reinforced Energy Barrier.
  findings:
  - statement: Sec63 and the lumenal chaperone BiP act as auxiliary translocation components during chaperone-mediated Sec61 channel gating for import of small presecretory proteins; the SEC63 J-domain (H132) is required for efficient translocation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes SEC63's J-domain/BiP-cooperative role in Sec61 channel gating and small-precursor translocation.
- id: PMID:36459117
  title: Signal sequences encode information for protein folding in the endoplasmic
    reticulum.
  findings:
  - statement: Marginally hydrophobic signal sequences and transmembrane domains cause
      transient retention at the Sec61 translocon and require luminal BiP for efficient
      translocation. Sec63 is co-translationally recruited to the translocation site and
      mediates BiP binding to incoming polypeptides, which releases translocationally
      paused nascent chains and ensures proper folding in the ER; increasing signal-sequence
      hydrophobicity bypasses Sec63/BiP dependence.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:36459117, J Cell Biol 2022, doi:10.1083/jcb.202203070).
      Directly supports SEC63's J-domain/BiP-recruitment co-chaperone mechanism and its
      role in translocating weak/marginally-hydrophobic signal-sequence substrates. Not
      in publications/ cache, so reference id added without verbatim supporting_text.
- id: PMID:37122003
  title: Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate
    hepatocellular carcinoma metastasis upon endoplasmic reticulum stress.
  findings:
  - statement: In hepatocellular carcinoma, ER stress activates SEC63 via IRE1alpha-mediated
      phosphorylation at T537; SEC63 stabilizes ACLY (ATP-citrate lyase) to increase acetyl-CoA
      and lipid biosynthesis, and also enters the nucleus to coordinate with ACLY in
      epigenetically upregulating Snail1, promoting metastasis. SEC63 is upregulated in HCC,
      correlates with ACLY, and predicts unfavorable prognosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:37122003, J Exp Clin Cancer Res 2023, doi:10.1186/s13046-023-02656-7).
      Reports a non-canonical, stress-responsive signaling/metabolic role for SEC63 (IRE1alpha-SEC63-ACLY
      axis) beyond its core translocon co-chaperone function; informative but not core.
      Abstract-only (not cached), so no verbatim supporting_text added to annotations.
- id: PMID:38689396
  title: Genetic Analysis of Severe Polycystic Liver Disease in Japan.
  findings:
  - statement: In a Japanese cohort of 49 patients with severe polycystic liver disease
      (height-adjusted total liver volume >1800 mL/m), 44/49 (90%) carried pathogenic or
      suspected pathogenic variants in polycystic disease genes; SEC63 accounted for 1/44
      (2%) of genetically solved cases, supporting its inclusion in diagnostic ADPLD gene panels.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:38689396, Kidney360 2024, doi:10.34067/KID.0000000000000461).
      Recent clinical-genetics cohort confirming SEC63 as a recurrent (if minor) cause of
      autosomal dominant polycystic liver disease; corroborates the disease association
      already noted in the review. Abstract-only (not cached); reference added without
      verbatim supporting_text.
- id: PMID:32133789
  title: Identification of signal peptide features for substrate specificity in human
    Sec62/Sec63-dependent ER protein import.
  findings:
  - statement: In intact human cells, 22 novel Sec62/Sec63-dependent substrates were
      identified in addition to ERj3; SEC62/SEC63 clients share signal peptides with longer
      but less hydrophobic H-regions and lower C-region polarity, and a slowly gating signal
      peptide combined with a downstream positively charged cluster is decisive for the
      Sec62/Sec63 requirement. The Sec62/Sec63 complex may support Sec61 opening by direct
      interaction with the cytosolic N-terminus of Sec61alpha or via recruitment of BiP
      to ER-lumenal loop 7 of Sec61alpha; these insights inform the etiology of SEC63-linked
      polycystic liver disease.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:32133789, FEBS J 2020, doi:10.1111/febs.15274;
      published version of the Schorr et al. 2019 bioRxiv preprint doi:10.1101/867762).
      Directly establishes the SEC62/SEC63 substrate-specificity rules and the BiP-recruitment
      gating mechanism, and explicitly links these to SEC63 polycystic liver disease. Not
      in publications/ cache, so reference id added without verbatim supporting_text.
- id: PMID:41009394
  title: Rules of Engagement for Components of Membrane Protein Biogenesis at the Human
    Endoplasmic Reticulum.
  findings:
  - statement: Review/article hybrid combining siRNA depletion of ER targeting and insertion
      components (including SEC62/SEC63) with label-free quantitative proteomics to define
      client types and rules of engagement, framing SEC63 as a substrate-selective Sec61
      translocon accessory/co-chaperone.
    reference_section_type: OTHER
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:41009394, Int J Mol Sci 2025, doi:10.3390/ijms26188823).
      Recent authoritative synthesis of human ER protein-biogenesis components including
      SEC63. Not in publications/ cache; reference id added without verbatim supporting_text.
- id: file:human/SEC63/SEC63-uniprot.txt
  title: UniProt entry Q9UGP8 (SEC63_HUMAN, DNAJC23), Translocation protein SEC63 homolog
  findings:
  - statement: SEC63 mediates cotranslational and post-translational transport of precursors across the ER, cooperates with SEC62 and HSPA5/BiP to import small presecretory proteins into the Sec61 channel; multi-pass ER membrane protein with a luminal DnaJ J-domain (104-165); required for PKD1 biogenesis; LoF variants cause PCLD2.
    reference_section_type: OTHER
core_functions:
- description: ER-membrane DnaJ/Hsp40-type co-chaperone of the Sec61 translocon whose luminal J-domain recruits and stimulates the ATPase activity of the ER Hsp70 BiP (HSPA5) to drive translocation of precursor polypeptides into the ER lumen.
  directly_involved_in:
  - id: GO:0031204
    label: post-translational protein targeting to membrane, translocation
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/SEC63/SEC63-uniprot.txt
    supporting_text: May cooperate with SEC62 and HSPA5/BiP to facilitate targeting of small presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen
  - reference_id: PMID:29719251
    supporting_text: Sec63 and the lumenal chaperone BiP act as auxiliary translocation components
- description: Auxiliary subunit of the SEC62-SEC63 complex of the ER translocon that supports cotranslational and post-translational import of precursor polypeptides into the endoplasmic reticulum.
  in_complex:
    id: GO:0031207
    label: Sec62/Sec63 complex
  supported_by:
  - reference_id: file:human/SEC63/SEC63-uniprot.txt
    supporting_text: different auxiliary components such as SEC62 and SEC63
  - reference_id: PMID:10799540
    supporting_text: a membrane protein complex that consists of the Sec61p complex and the Sec62p-Sec63p subcomplex
  directly_involved_in:
  - id: GO:0006620
    label: post-translational protein targeting to endoplasmic reticulum membrane
  - id: GO:0031204
    label: post-translational protein targeting to membrane, translocation
proposed_new_terms: []
suggested_questions:
- question: Should SEC63 carry an explicit Hsp70/BiP co-chaperone or heat-shock-protein-binding molecular-function annotation to capture its J-domain stimulation of BiP ATPase, which the current GOA does not represent?
- question: How does the SEC63-nucleoredoxin (Wnt-pathway) interaction mechanistically connect translocon function to the cystogenesis seen in PCLD2?
suggested_experiments:
- description: Reconstitute BiP ATPase stimulation by wild-type versus HPD-mutant (H132Q) SEC63 J-domain and correlate with translocation efficiency of defined precursors to establish the J-domain/BiP molecular function.
- description: Express PCLD2 truncating SEC63 variants and quantify polycystin-1 (PKD1) biogenesis/trafficking and BiP recruitment at the translocon to link the molecular defect to disease.