id: P61009
gene_symbol: SPCS3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SPCS3 (signal peptidase complex subunit 3, also SPC22/23, the microsomal signal peptidase 22/23 kDa subunit) is a 180 aa single-pass type II endoplasmic reticulum membrane protein that is one of the three non-catalytic accessory subunits (with SPCS1 and SPCS2) of the eukaryotic ER signal peptidase complex (SPC). The SPC removes N-terminal signal sequences from secretory and membrane preproteins as they are translocated into the ER lumen; catalysis resides in the SEC11A or SEC11C subunits. SPCS3 has a single N-terminal transmembrane helix and a large lumenal domain, and although not catalytic itself it is essential for SPC catalytic activity, thought to stabilize and position the catalytic center near the lumenal surface of the membrane. Together with the other subunits it contributes to the transmembrane window that locally thins the ER bilayer and sets the complex's selectivity for short signal-peptide hydrophobic regions. SPCS3 also acts as a host factor required for efficient production of flaviviruses (West Nile, Japanese encephalitis, Dengue type 2, and yellow fever viruses).
existing_annotations:
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: SPCS3 is a constitutive accessory subunit of the ER signal peptidase complex; the phylogenetic assignment reflects its core identity.
    action: ACCEPT
    reason: Core complex membership, supported experimentally by cryo-EM and ComplexPortal curation.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3'
- term:
    id: GO:0045047
    label: protein targeting to ER
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SPCS3 does not target proteins to the ER; as part of the signal peptidase complex it acts on already-translocating substrates to cleave the signal peptide. The phylogenetic term is mis-specified; the accurate process is signal peptide processing.
    action: MODIFY
    reason: The SPC acts downstream of ER targeting. UniProt/ComplexPortal annotate this activity as signal peptide processing (GO:0006465).
    proposed_replacement_terms:
    - id: GO:0006465
      label: signal peptide processing
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA machine-learning assignment of ER localization; correct but less specific than the ER membrane term.
    action: ACCEPT
    reason: Correct localization; the more specific GO:0005789 (ER membrane) better captures the multi-pass topology.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based electronic assignment to the signal peptidase complex, consistent with experimental evidence.
    action: ACCEPT
    reason: Correct core complex membership; redundant with experimental IPI/IBA evidence.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SPCS3 is an ER membrane protein; the subcellular-location-based electronic annotation is correct and reflects the core localization.
    action: ACCEPT
    reason: Core localization, supported by structure (PMID:34388369) and ortholog topology.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane localization, a parent of the more informative ER membrane term.
    action: KEEP_AS_NON_CORE
    reason: Correct but uninformative; the specific GO:0005789 (ER membrane) better captures SPCS3 localization.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: Single-pass type II membrane protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  qualifier: enables
  review:
    summary: High-throughput interaction proteomics capturing SPCS3 binding to ATXN1; a real interaction but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome capture; bare protein binding is uninformative and not the core function.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'P61009; P54253: ATXN1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput human interactome capturing SPCS3 binding to SEC11C; a genuine intra-complex interaction but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interaction (SEC11C) but bare protein binding is uninformative; complex membership is captured by GO:0005787.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'P61009; Q9BY50: SEC11C'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegenerative-disease interactome capturing SPCS3 binding to HTT/ATXN1; real interactions but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome capture; bare protein binding is uninformative and not the core function.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'P61009; P42858: HTT'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Proteome-scale BioPlex interactome capturing SPCS3 binding to SEC11A/SEC11C; genuine intra-complex interactions but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'P61009; P67812: SEC11A'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34388369
  qualifier: enables
  review:
    summary: Interactions with the other SPC subunits (SEC11A/SEC11C, SPCS1, SPCS2) captured during the structural study; bare protein binding is uninformative although the intra-complex interactions are genuine.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: Within the complex, interacts with SEC11A or SEC11C and SPCS1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome capturing SPCS3 binding to SEC11A/SEC11C; genuine intra-complex interactions but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'P61009; Q9BY50: SEC11C'
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IPI
  original_reference_id: PMID:34388369
  qualifier: part_of
  review:
    summary: ComplexPortal annotation of SPCS3 as a component of the signal peptidase complex, based on the cryo-EM structure of the human SPC.
    action: ACCEPT
    reason: Definitive experimental (structural) evidence for SPC membership; the core identity of SPCS3.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: the human SPC exists in two functional paralogs with distinct proteolytic subunits
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: located_in
  review:
    summary: Direct (structural) evidence places SPCS3 in the ER membrane as part of the SPC; correct core localization.
    action: ACCEPT
    reason: IDA-supported ER membrane localization consistent with the membrane-embedded SPC structure.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: a transmembrane window collectively formed by all subunits locally thins the bilayer
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: involved_in
  review:
    summary: SPCS3 participates in proteolytic processing of preproteins as part of the signal peptidase complex; the more precise term is signal peptide processing (GO:0006465).
    action: ACCEPT
    reason: Correct involvement in the SPC's proteolytic processing of substrates; supported by the structural study and ComplexPortal curation. The core process is signal peptide processing.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: the determinants for signal peptide cleavage
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer of ER membrane localization from an ortholog; consistent with stronger experimental evidence.
    action: ACCEPT
    reason: Correct core localization, redundant with IDA/IEA evidence.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0019082
    label: viral protein processing
  evidence_type: IMP
  original_reference_id: PMID:27383988
  qualifier: involved_in
  review:
    summary: A genome-wide CRISPR screen showed SPCS3 (with other SPCS proteins) is required for proper processing of flavivirus structural proteins and virion production; a real experimental phenotype but a secondary host-pathogen role.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported viral host-factor role; secondary to SPCS3's core function in cellular signal peptide processing.
    supported_by:
    - reference_id: PMID:27383988
      supporting_text: a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IDA
  original_reference_id: PMID:27499293
  qualifier: involved_in
  review:
    summary: Experimental annotation linking SPCS3 to proteolysis, made by a curator with access to the full text (a study of ER translocation and regulated membrane-protein/CREB3L1 cleavage). The general proteolysis term reflects SPCS3's role in the proteolytic signal peptidase complex; SPCS3 is essential for SPC catalytic activity though not itself the protease.
    action: KEEP_AS_NON_CORE
    reason: General parent term; SPCS3 is a non-catalytic but essential subunit of the proteolytic SPC. The informative process is GO:0006465 signal peptide processing. Experimental IDA retained (full text not in cache), kept as non-core given the more specific available terms.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-422051
  qualifier: located_in
  review:
    summary: Reactome curation of SPCS3 ER membrane localization (preproghrelin signal peptide cleavage context).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9918795
  qualifier: located_in
  review:
    summary: Reactome curation of SPCS3 ER membrane localization (flavivirus signalase cleavage context).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9918871
  qualifier: located_in
  review:
    summary: Reactome curation of SPCS3 ER membrane localization (signalase cleavage context).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: Direct fluorescent fusion-protein localization (LIFEdb) placing SPCS3 in the ER; correct though less specific than ER membrane.
    action: ACCEPT
    reason: IDA-supported ER localization consistent with the ER membrane annotations.
    supported_by:
    - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  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:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interaction proteomics; source of a bare protein binding annotation (ATXN1), not relevant to SPCS3's core function.
- id: PMID:27383988
  title: A CRISPR screen defines a signal peptide processing pathway required by flaviviruses.
  findings:
  - statement: SPCS3 (with other SPCS proteins) is required for proper cleavage of flavivirus structural proteins and virion production.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Genome-wide CRISPR screen establishing the flavivirus host-factor role; secondary to the core cellular function.
- id: PMID:27499293
  title: Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix.
  findings:
  - statement: Study of regulated alternative translocation (TM4SF20/CREB3L1 cleavage); cited by UniProt as experimental support for SPCS3's role in the proteolytic signal peptidase complex.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Abstract-only in cache; full text not available. Source of the SPCS3 IDA proteolysis annotation made by a curator with full-text access; retained per guidelines.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput human interactome; source of a bare protein binding annotation (SEC11C), an intra-complex interaction.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput neurodegenerative-disease interactome; source of bare protein binding annotations (HTT, ATXN1).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex proteome-scale interactome; source of bare protein binding annotations (SEC11A/SEC11C), intra-complex interactions.
- id: PMID:34388369
  title: Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage.
  findings:
  - statement: Cryo-EM structures of the two human SPC paralogs identify SPCS3 as an accessory subunit; the complex forms a transmembrane window that locally thins the ER bilayer, generating specificity for signal-peptide hydrophobic-segment length.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structural study establishing SPCS3 as an accessory SPC subunit; basis for ComplexPortal annotations.
- id: PMID:39261662
  title: Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production.
  findings:
  - statement: In human (THP-1-derived) macrophages, SPCS3 was identified by proteomics and functional validation as a chikungunya virus (CHIKV) E1 glycoprotein-binding host protein with anti-CHIKV (restriction-factor) activity; the positively selected CHIKV E1 residue V220 is indispensable for virion production and its mutation attenuates E1 interaction with the host restriction factors SPCS3 and eIF3k, indicating a host-virus evolutionary arms race late in the viral life cycle.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:39261662, doi:10.1038/s44318-024-00193-3, EMBO J 2024). Notable new finding - SPCS3 acts as an antiviral restriction factor against CHIKV (an alphavirus, distinct from the flaviviral host-factor role) via E1 binding; Falcon reports this is peptidase-independent (overexpression did not alter CHIKV polyglycoprotein cleavage). A secondary host-pathogen/innate-immunity role, not the core SPC function. Not in publications cache, so no verbatim supporting_text added.
- id: PMID:38230952
  title: Landscape of protein-protein interactions during hepatitis C virus assembly and release.
  findings:
  - statement: An affinity-purification mass-spectrometry interactome of HCV-infected cells engaged SPC components near viral envelope/assembly proteins, with SPCS3 reported in the HCV E2 accessory interactome; the authors note SPC subunits SPCS1 and SPCS3 were previously recognized as important for flavivirus particle production and HCV.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:38230952, doi:10.1128/spectrum.02562-22). High-throughput AP-MS interactome placing SPCS3 in the HCV E2 accessory interactome; secondary host-pathogen context, not core function. Not in publications cache, so no verbatim supporting_text added.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of bare protein binding annotations (SEC11A/SEC11C), intra-complex interactions.
- id: Reactome:R-HSA-422051
  title: Cleavage of the signal peptide of Preproghrelin
  findings: []
- id: Reactome:R-HSA-9918795
  title: Signalase cleaves prM-E-NS1-NS2A
  findings: []
- id: Reactome:R-HSA-9918871
  title: Signalase cleaves prepro-NS4B
  findings: []
- id: file:human/SPCS3/SPCS3-uniprot.txt
  title: UniProt entry P61009 (SPCS3_HUMAN), signal peptidase complex subunit 3
  findings:
  - statement: Essential non-catalytic accessory subunit of the ER signal peptidase complex (SPC-A with SEC11A and SPC-C with SEC11C, each also containing SPCS1 and SPCS2); single-pass type II ER membrane protein with a large lumenal domain; essential for SPC catalytic activity by stabilizing/positioning the active center; flavivirus host factor.
    reference_section_type: OTHER
core_functions:
- description: Essential non-catalytic accessory subunit of the ER signal peptidase complex that stabilizes and positions the catalytic center, required for the complex's signal peptide processing of secretory and membrane preproteins.
  supported_by:
  - reference_id: file:human/SPCS3/SPCS3-uniprot.txt
    supporting_text: Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface
  - reference_id: PMID:34388369
    supporting_text: a transmembrane window collectively formed by all subunits locally thins the bilayer
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  contributes_to_molecular_function:
    id: GO:0009003
    label: signal peptidase activity
  in_complex:
    id: GO:0005787
    label: signal peptidase complex
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
proposed_new_terms: []
suggested_questions:
- question: By what structural mechanism does the SPCS3 lumenal domain become essential for SEC11 catalytic activity, in contrast to the dispensable SPCS1?
- question: Is the flavivirus dependence on SPCS3 attributable to its general signal-peptidase role or to substrate-specific processing of viral structural proteins?
suggested_experiments:
- description: Reconstitute SPC with and without SPCS3 and measure signal-peptidase activity to quantify its requirement and define which substrate classes most depend on it.
- description: Structure-guided mutagenesis of the SPCS3 lumenal domain at the SEC11 interface, with activity assays, to test the proposed active-center stabilization mechanism.