id: Q9Y6A9
gene_symbol: SPCS1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SPCS1 (signal peptidase complex subunit 1, also SPC12, the microsomal signal peptidase 12 kDa subunit) is a small (169 aa) multi-pass endoplasmic reticulum membrane protein that is one of the three non-catalytic accessory subunits (with SPCS2 and SPCS3) 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; its catalytic activity resides in the SEC11A or SEC11C subunits, and SPCS1 is dispensable for enzymatic cleavage. SPCS1 spans the ER membrane twice with both termini facing the cytosol and only minimal lumenal exposure, and together with the other subunits it shapes a transmembrane "window" that locally thins the lipid bilayer, contributing to substrate selectivity for signal-peptide hydrophobic regions shorter than about 18-20 residues. Beyond its housekeeping role in signal peptide processing, SPCS1 acts as a host factor exploited by flaviviruses (West Nile, Dengue, Zika, yellow fever, Japanese encephalitis viruses) and hepatitis C virus, where it promotes post-translational processing of viral structural proteins and assembly of infectious virions through interactions with viral membrane proteins such as HCV NS2/E2 and flaviviral NS2B.
existing_annotations:
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: SPCS1 is a constitutive accessory subunit of the ER signal peptidase complex; phylogenetic assignment is correct and reflects the core identity of the protein.
    action: ACCEPT
    reason: Core complex membership, strongly supported experimentally (cryo-EM, ComplexPortal) and by UniProt.
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-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: SPCS1 does not target nascent proteins to the ER (that is the role of SRP and the Sec61 translocon); it acts after translocation as part of the signal peptidase complex that cleaves the signal peptide. The phylogenetic term is mis-specified; the accurate process is signal peptide processing.
    action: MODIFY
    reason: The SPC functions downstream of ER targeting, on already-translocating substrates, to cleave the signal peptide. UniProt/ComplexPortal annotate this activity as signal peptide processing (GO:0006465), not protein targeting to ER.
    proposed_replacement_terms:
    - id: GO:0006465
      label: signal peptide processing
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-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: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/SPCS1/SPCS1-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: SPCS1 is a multi-pass ER membrane protein; the subcellular-location-based electronic annotation is correct and reflects the core localization.
    action: ACCEPT
    reason: Core localization, supported by experimental topology (PMID:8632014) and structure (PMID:34388369).
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-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 SPCS1 localization.
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24009510
  qualifier: enables
  review:
    summary: IntAct capture of SPCS1 interaction with hepatitis C virus NS2; a real host-pathogen interaction but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real experimental interaction (HCV NS2/E2) but bare protein binding is uninformative per curation guidelines and reflects a secondary viral role.
    supported_by:
    - reference_id: PMID:24009510
      supporting_text: SPCS1 was found to interact with both NS2 and E2
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IPI
  original_reference_id: PMID:34388369
  qualifier: part_of
  review:
    summary: ComplexPortal annotation of SPCS1 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; this is the core identity of SPCS1.
    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 SPCS1 in the ER membrane as part of the SPC; correct core localization.
    action: ACCEPT
    reason: IDA-supported ER membrane localization consistent with the multi-pass topology and 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: SPCS1 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/SPCS1/SPCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- 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, SPCS2, SPCS3) captured during the structural study; the bare protein binding term is uninformative although the underlying intra-complex interactions are genuine and functionally relevant.
    action: KEEP_AS_NON_CORE
    reason: Real intra-complex interactions (SPCS2, SPCS3, SEC11A/C) but bare protein binding is uninformative; the SPC membership is already captured by GO:0005787.
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-uniprot.txt
      supporting_text: Within the complex, interacts with SPCS2 and SPCS3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29593046
  qualifier: enables
  review:
    summary: IntAct capture of SPCS1 interaction with flaviviral NS2B; a real host-pathogen interaction but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real experimental interaction (flavivirus NS2B) but bare protein binding is uninformative and reflects a secondary viral role.
    supported_by:
    - reference_id: PMID:29593046
      supporting_text: SPCS1 was found to interact with nonstructural protein 2B (NS2B)
- term:
    id: GO:0019068
    label: virion assembly
  evidence_type: IMP
  original_reference_id: PMID:24009510
  qualifier: involved_in
  review:
    summary: SPCS1 knockdown markedly reduces production of infectious HCV by impairing formation of the membrane-associated NS2-E2 complex; a real experimental phenotype but a host-pathogen (secondary) role rather than SPCS1's core cellular function.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported viral host-factor phenotype; not the core housekeeping function of SPCS1.
    supported_by:
    - reference_id: PMID:24009510
      supporting_text: SPCS1 plays a key role in the formation of the membrane-associated NS2-E2 complex via its interaction with NS2 and E2
    - reference_id: PMID:35130329
- term:
    id: GO:0019068
    label: virion assembly
  evidence_type: IMP
  original_reference_id: PMID:29593046
  qualifier: involved_in
  review:
    summary: SPCS1 loss reduces JEV virion assembly through interaction with NS2B; a real experimental viral phenotype but a secondary host-pathogen role.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported viral host-factor phenotype; not the core cellular function.
    supported_by:
    - reference_id: PMID:29593046
      supporting_text: The loss of SPCS1 function markedly reduced intracellular virion assembly and the production of infectious JEV particles
- 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 SPCS1 is required for proper cleavage of flavivirus structural proteins (prM and E); a real experimental phenotype but a secondary host-pathogen role.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported viral host-factor role in processing flaviviral structural proteins; secondary to SPCS1'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:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-422051
  qualifier: located_in
  review:
    summary: Reactome curation of SPCS1 ER membrane localization (preproghrelin signal peptide cleavage context).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-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 SPCS1 ER membrane localization (flavivirus signalase cleavage context).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-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 SPCS1 ER membrane localization (signalase cleavage context).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/SPCS1/SPCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: TAS
  original_reference_id: PMID:8632014
  qualifier: part_of
  review:
    summary: Early biochemical/topology study identifying SPC12 (SPCS1) as the 12-kDa subunit of the mammalian signal peptidase complex.
    action: ACCEPT
    reason: Correct core complex membership; the historical reference that cloned and characterized SPC12 as an SPC subunit.
    supported_by:
    - reference_id: PMID:8632014
      supporting_text: We have determined the cDNA sequence of the remaining 12-kDa subunit (SPC12)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:8632014
  qualifier: located_in
  review:
    summary: Direct topology study placing SPC12 (SPCS1) in the ER (microsomal) membrane, spanning it twice with cytosol-facing termini.
    action: ACCEPT
    reason: IDA-supported ER membrane localization with experimentally determined topology.
    supported_by:
    - reference_id: PMID:8632014
      supporting_text: Both polypeptides span the membrane twice with their N and C termini facing the cytosol
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: TAS
  original_reference_id: PMID:8632014
  qualifier: involved_in
  review:
    summary: General proteolysis annotation derived from SPCS1 being a subunit of the signal peptidase complex. SPCS1 itself is non-catalytic, and the cytosol-facing topology argues it is not directly involved in the lumenal cleavage; the specific process is signal peptide processing.
    action: KEEP_AS_NON_CORE
    reason: Generic parent term; SPCS1 is a non-catalytic accessory subunit and the cited paper explicitly concluded it is likely involved in processes other than enzymatic signal-sequence cleavage. The informative process term is GO:0006465 signal peptide processing.
    supported_by:
    - reference_id: PMID:8632014
      supporting_text: SPC12 and SPC25 are likely to be involved in processes other than the enzymatic cleavage of the signal sequence
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: PMID:8632014
  title: Membrane topology of the 12- and the 25-kDa subunits of the mammalian signal peptidase complex.
  findings:
  - statement: SPC12 (SPCS1) is the 12-kDa subunit of the mammalian SPC; it spans the membrane twice with N and C termini facing the cytosol and minimal lumenal domains, indicating a non-catalytic role.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes SPCS1 (SPC12) topology and SPC membership and the inference that it is not the catalytic subunit.
- id: PMID:24009510
  title: Signal peptidase complex subunit 1 participates in the assembly of hepatitis C virus through an interaction with E2 and NS2.
  findings:
  - statement: SPCS1 interacts with HCV NS2 and E2 and is required for assembly of infectious HCV particles, without affecting structural-protein processing, host secretion, entry, RNA replication, or release.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the HCV NS2/E2 interaction and virion-assembly host-factor role; secondary to SPCS1's core SPC function.
- id: PMID:27383988
  title: A CRISPR screen defines a signal peptide processing pathway required by flaviviruses.
  findings:
  - statement: SPCS1 is required for proper cleavage of flavivirus structural proteins (prM, E) and secretion of viral particles; loss reduces yield of WNV, DENV, ZIKV, YFV, JEV, and HCV.
    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:29593046
  title: Host Factor SPCS1 Regulates the Replication of Japanese Encephalitis Virus through Interactions with Transmembrane Domains of NS2B.
  findings:
  - statement: SPCS1 interacts with the transmembrane domains of flaviviral NS2B and is required for post-translational processing of JEV proteins and virion assembly, but not entry, RNA replication, or translation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Mechanistic study of the flavivirus host-factor role via NS2B interaction; reaffirms SPCS1 is non-catalytic.
- 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 (SEC11A and SEC11C variants); the active site abuts the ER membrane where a transmembrane window collectively formed by all subunits locally thins the bilayer, generating specificity based on signal-peptide hydrophobic-segment length.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structural study establishing SPCS1 as an accessory SPC subunit and the membrane-thinning architecture; basis for ComplexPortal annotations.
- id: PMID:35130329
  title: SPCS1-Dependent E2-p7 processing determines HCV Assembly efficiency.
  findings:
  - statement: Loss of SPCS1 specifically impairs SPC-mediated processing of the HCV E2-p7 junction (a suboptimal cleavage site); efficient separation of E2 and p7 renders SPCS1 dispensable for assembly, establishing that SPCS1 facilitates assembly by enhancing presentation of the suboptimal E2-p7 junction to the SPC active site, paralleling its role at the flaviviral C-prM junction.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:35130329, doi:10.1371/journal.ppat.1010310). Mechanistic study of the SPCS1 HCV host-factor role; supports the existing virion-assembly annotation. Secondary to the core SPC function. Not in publications cache, so no verbatim supporting_text added.
- id: PMID:33577859
  title: Signal peptidase complex subunit 1 is an essential Zika virus host factor in placental trophoblasts.
  findings:
  - statement: A pooled CRISPR/Cas9 screen in placental trophoblasts identified ER membrane complex and signal peptide processing genes as Zika virus host factors, and validated SPCS1 as crucial for ZIKV replication in trophoblasts.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:33577859, doi:10.1016/j.virusres.2021.198338). Corroborates the flavivirus host-factor role of SPCS1 in a placental-trophoblast context; secondary to the core SPC function. Not in publications cache, so no verbatim supporting_text added.
- 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/SPCS1/SPCS1-uniprot.txt
  title: UniProt entry Q9Y6A9 (SPCS1_HUMAN), signal peptidase complex subunit 1
  findings:
  - statement: Non-catalytic accessory subunit of the ER signal peptidase complex (SPC-A with SEC11A and SPC-C with SEC11C, each also containing SPCS2 and SPCS3); multi-pass ER membrane protein; dispensable for SPC enzymatic activity; host factor for flavivirus/HCV structural-protein processing and assembly.
    reference_section_type: OTHER
core_functions:
- description: Non-catalytic accessory subunit of the ER signal peptidase complex, contributing to the architecture (membrane-thinning transmembrane window) and substrate selectivity of the complex that cleaves signal peptides from secretory and membrane preproteins.
  supported_by:
  - reference_id: file:human/SPCS1/SPCS1-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'
  - 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: Does SPCS1 modulate the substrate range or efficiency of the signal peptidase complex (e.g., selectivity for particular signal-peptide hydrophobic-region lengths), or is it purely structural?
- question: Is the flavivirus/HCV dependence on SPCS1 a direct consequence of its signal-peptidase accessory role, or a separable function mediated by direct binding to viral transmembrane proteins (NS2B, NS2/E2)?
suggested_experiments:
- description: Reconstitute the SEC11A- and SEC11C-paralog signal peptidase complexes in vitro with and without SPCS1 and measure cleavage kinetics across a panel of substrates with varying signal-peptide h-region lengths to define SPCS1's contribution to activity and selectivity.
- description: Targeted SPCS1 degradation (e.g., degron) followed by quantitative N-terminomics to identify cellular preproteins whose signal-peptide cleavage depends on SPCS1.