Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005787 signal peptidase complex	IBA GO_REF:0000033	ACCEPT	Summary: SPCS3 is a constitutive accessory subunit of the ER signal peptidase complex; the phylogenetic assignment reflects its core identity. Reason: Core complex membership, supported experimentally by cryo-EM and ComplexPortal curation. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3
GO:0045047 protein targeting to ER	IBA GO_REF:0000033	MODIFY	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. Reason: The SPC acts downstream of ER targeting. UniProt/ComplexPortal annotate this activity as signal peptide processing (GO:0006465). Proposed replacements: signal peptide processing Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine-learning assignment of ER localization; correct but less specific than the ER membrane term. Reason: Correct localization; the more specific GO:0005789 (ER membrane) better captures the multi-pass topology. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005787 signal peptidase complex	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic assignment to the signal peptidase complex, consistent with experimental evidence. Reason: Correct core complex membership; redundant with experimental IPI/IBA evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: SPCS3 is an ER membrane protein; the subcellular-location-based electronic annotation is correct and reflects the core localization. Reason: Core localization, supported by structure (PMID:34388369) and ortholog topology. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0016020 membrane	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Generic membrane localization, a parent of the more informative ER membrane term. Reason: Correct but uninformative; the specific GO:0005789 (ER membrane) better captures SPCS3 localization. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Single-pass type II membrane protein
GO:0005515 protein binding	IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis...	KEEP AS NON CORE	Summary: High-throughput interaction proteomics capturing SPCS3 binding to ATXN1; a real interaction but the bare protein binding term is uninformative. Reason: High-throughput interactome capture; bare protein binding is uninformative and not the core function. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; P54253: ATXN1
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: High-throughput human interactome capturing SPCS3 binding to SEC11C; a genuine intra-complex interaction but the bare protein binding term is uninformative. Reason: Real intra-complex interaction (SEC11C) but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; Q9BY50: SEC11C
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Neurodegenerative-disease interactome capturing SPCS3 binding to HTT/ATXN1; real interactions but the bare protein binding term is uninformative. Reason: High-throughput interactome capture; bare protein binding is uninformative and not the core function. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; P42858: HTT
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Proteome-scale BioPlex interactome capturing SPCS3 binding to SEC11A/SEC11C; genuine intra-complex interactions but the bare protein binding term is uninformative. Reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; P67812: SEC11A
GO:0005515 protein binding	IPI PMID:34388369 Structure of the human signal peptidase complex reveals the ...	KEEP AS NON CORE	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. Reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Within the complex, interacts with SEC11A or SEC11C and SPCS1
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-map interactome capturing SPCS3 binding to SEC11A/SEC11C; genuine intra-complex interactions but the bare protein binding term is uninformative. Reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; Q9BY50: SEC11C
GO:0005787 signal peptidase complex	IPI PMID:34388369 Structure of the human signal peptidase complex reveals the ...	ACCEPT	Summary: ComplexPortal annotation of SPCS3 as a component of the signal peptidase complex, based on the cryo-EM structure of the human SPC. Reason: Definitive experimental (structural) evidence for SPC membership; the core identity of SPCS3. Supporting Evidence: PMID:34388369 the human SPC exists in two functional paralogs with distinct proteolytic subunits
GO:0005789 endoplasmic reticulum membrane	IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ...	ACCEPT	Summary: Direct (structural) evidence places SPCS3 in the ER membrane as part of the SPC; correct core localization. Reason: IDA-supported ER membrane localization consistent with the membrane-embedded SPC structure. Supporting Evidence: PMID:34388369 a transmembrane window collectively formed by all subunits locally thins the bilayer
GO:0016485 protein processing	IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ...	ACCEPT	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). 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. Supporting Evidence: PMID:34388369 the determinants for signal peptide cleavage
GO:0005789 endoplasmic reticulum membrane	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of ER membrane localization from an ortholog; consistent with stronger experimental evidence. Reason: Correct core localization, redundant with IDA/IEA evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0019082 viral protein processing	IMP PMID:27383988 A CRISPR screen defines a signal peptide processing pathway ...	KEEP AS NON CORE	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. Reason: Experimentally supported viral host-factor role; secondary to SPCS3's core function in cellular signal peptide processing. Supporting Evidence: PMID:27383988 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
GO:0006508 proteolysis	IDA PMID:27499293 Inverting the Topology of a Transmembrane Protein by Regulat...	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-422051	ACCEPT	Summary: Reactome curation of SPCS3 ER membrane localization (preproghrelin signal peptide cleavage context). Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9918795	ACCEPT	Summary: Reactome curation of SPCS3 ER membrane localization (flavivirus signalase cleavage context). Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9918871	ACCEPT	Summary: Reactome curation of SPCS3 ER membrane localization (signalase cleavage context). Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000054	ACCEPT	Summary: Direct fluorescent fusion-protein localization (LIFEdb) placing SPCS3 in the ER; correct though less specific than ER membrane. Reason: IDA-supported ER localization consistent with the ER membrane annotations. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane

Core Functions

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.

Molecular Function:

structural molecule activity

Cellular Locations:

endoplasmic reticulum membrane

In Complex:

signal peptidase complex

Supporting Evidence:

file:human/SPCS3/SPCS3-uniprot.txt
Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface
PMID:34388369
a transmembrane window collectively formed by all subunits locally thins the bilayer

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

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:0000054

Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:25959826

Quantitative interaction proteomics of neurodegenerative disease proteins.

PMID:27383988

A CRISPR screen defines a signal peptide processing pathway required by flaviviruses.

SPCS3 (with other SPCS proteins) is required for proper cleavage of flavivirus structural proteins and virion production.

PMID:27499293

Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix.

Study of regulated alternative translocation (TM4SF20/CREB3L1 cleavage); cited by UniProt as experimental support for SPCS3's role in the proteolytic signal peptidase complex.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34388369

Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage.

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.

PMID:39261662

Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production.

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.

PMID:38230952

Landscape of protein-protein interactions during hepatitis C virus assembly and release.

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.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-422051

Cleavage of the signal peptide of Preproghrelin

Reactome:R-HSA-9918795

Signalase cleaves prM-E-NS1-NS2A

Reactome:R-HSA-9918871

Signalase cleaves prepro-NS4B

file:human/SPCS3/SPCS3-uniprot.txt

UniProt entry P61009 (SPCS3_HUMAN), signal peptidase complex subunit 3

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.

Suggested Experiments

Experiment: Reconstitute SPC with and without SPCS3 and measure signal-peptidase activity to quantify its requirement and define which substrate classes most depend on it.

Experiment: Structure-guided mutagenesis of the SPCS3 lumenal domain at the SEC11 interface, with activity assays, to test the proposed active-center stabilization mechanism.

Deep Research

Falcon

(SPCS3-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 27 citations 2 artifacts 2026-06-12T03:39:40.259717

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000022 Figure 6I illustrates the human signal peptidase complex (SPC) embedded in a thinned membrane, acting as a "molecular ruler" for si (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human SPCS3 (UniProt P61009) — Functional Annotation

0) Target identity verification (mandatory)

The requested target, human SPCS3 (UniProt P61009), corresponds to signal peptidase complex subunit 3, historically termed SPC22/23 (based on apparent molecular weight), and is a conserved subunit of the endoplasmic reticulum (ER) signal peptidase complex (SPC). A key structural study explicitly maps SPC22/23 to SPCS3 and demonstrates that SPC22/23 is present in both human SPC paralogs (SPC-A and SPC-C) together with accessory subunits SPC12 (SPCS1) and SPC25 (SPCS2) plus a catalytic SEC11 protease paralog (SEC11A or SEC11C). This aligns with the UniProt description and avoids conflation with other “Spc3/Spc2” yeast proteins or SEC11 paralogs. (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4)

1) Key concepts and definitions (current understanding)

1.1 Signal peptides and signal peptidase complex (SPC)

Secretory and many membrane proteins are synthesized with an N-terminal signal peptide (SP) that targets the nascent chain to the ER. The signal peptidase complex (SPC) is an ER membrane-resident serine protease that removes signal peptides during ER translocation, enabling downstream folding, trafficking, secretion, and maturation of the cleaved protein product. (liaci2021structureofthe pages 1-3, zanotti2023characterisationofthe pages 53-57)

1.2 What SPCS3 is (and is not)

SPCS3 is not itself the catalytic protease. Instead, it is an essential SPC subunit (SPC22/23) that stabilizes and positions the catalytic SEC11 subunit’s active site and contributes to the membrane-embedded architecture that determines substrate selectivity. (liaci2021structureofthe pages 8-10, liaci2021structureofthe pages 10-12)

2) Molecular function, biochemical role, and mechanism

2.1 SPC composition and where SPCS3 fits

High-resolution structural proteomics and cryo-EM indicate the human SPC exists as two paralogous hetero-tetramers:
- SPC-A: SEC11A + SPC12 (SPCS1) + SPC25 (SPCS2) + SPC22/23 (SPCS3)
- SPC-C: SEC11C + SPC12 (SPCS1) + SPC25 (SPCS2) + SPC22/23 (SPCS3)
(liaci2021structureofthe pages 3-4, liaci2021structureofthe pages 1-3)

SPCS3 contributes a luminal β-sandwich (ASF1-like) domain that interacts with SEC11 and “embraces” its catalytic core, and it also provides transmembrane helices that participate in the complex’s membrane “window.” (liaci2021structureofthe pages 3-4)

2.2 Cellular localization and topology

The SPC is embedded in the ER membrane, with catalytic processing occurring at the luminal face. SPCS3 contains a luminal domain and contributes to a transmembrane architecture that positions the catalytic site at the membrane interface. SPCS3 is reported to be highly N-glycosylated at Asp141 in the HEK293-derived sample described, consistent with luminal exposure. (liaci2021structureofthe pages 3-4, liaci2021structureofthe pages 10-12)

2.3 Catalysis (what reaction is carried out?)

The SPC catalyzes peptide-bond hydrolysis at the signal peptide cleavage site of secretory-pathway precursors. Structural work defines the catalytic center (in SEC11A/C) as a Ser–His–Asp triad, and emphasizes that stabilization of this motif depends on the chaperone-like luminal domain of SPC22/23 (SPCS3). Thus, SPCS3 is mechanistically essential for efficient catalysis even though the scissile-bond chemistry is executed by SEC11. (liaci2021structureofthe pages 8-10, liaci2021structureofthe pages 10-12)

2.4 Substrate specificity: “TM window” and membrane thinning

A central mechanistic insight is that the SPC forms a lipid-filled transmembrane (TM) window collectively formed by all subunits. The TM helices of SEC11A/C and SPCS3 form the inner lining of this window, which locally thins the ER bilayer above the c-region binding pocket. This creates a physical “molecular ruler” that strongly favors short signal peptide hydrophobic segments (h-regions) and excludes longer transmembrane helices. (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12)

Quantitatively:
- Membrane thinning in simulations is ~26% on average. (liaci2021structureofthe pages 5-7)
- Mean SP h-region length reported is ~11 residues; eukaryotic SPC generally does not cleave SPs with h-regions longer than 18–20 aa. (liaci2021structureofthe pages 10-12)

These findings explain how the SPC can process thousands of diverse substrates with conserved selectivity principles. (liaci2021structureofthe pages 10-12)

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2023: SPC as a membrane-protein quality-control protease (noncanonical substrates)

A 2023 body of work argues that, beyond canonical co-translational SP removal, the SPC can act as a post-translocational quality-control enzyme for membrane proteins. In this model:
- The catalytic core is SEC11A/C + SPCS3.
- SPCS1 functions as a recruitment/exosite factor for noncanonical membrane substrates, helping present cryptic cleavage sites from longer TMDs that would otherwise be excluded by membrane thinning.
- A proteome-wide analysis predicted ~1,500 membrane proteins with putative internal “cryptic” SPC sites, and several multipass proteins were experimentally validated as noncanonical substrates (e.g., connexins, iRhom2, Hrd1), with links to ER stress adaptation and ERAD cooperation.
(zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60, zanotti2023characterisationofthe pages 1-8)

This reframes SPCS3 (as part of the catalytic core) as potentially relevant not only to protein biogenesis but also to membrane proteostasis.

3.2 2024: SPCS3 as an antiviral restriction factor for chikungunya virus (CHIKV)

A 2024 EMBO Journal study discovered an unexpected role for SPCS3 in innate antiviral restriction in human macrophage models:
- SPCS3 binds CHIKV glycoprotein E1 and shows anti-CHIKV activity.
- Importantly, SPCS3 overexpression did not alter CHIKV poly-glycoprotein cleavage, supporting a peptidase-independent antiviral mechanism.
- A positively selected viral residue (E1-V220) is critical for virion production in macrophages and modulates E1 interaction with SPCS3 (and eIF3k), consistent with host–virus evolutionary conflict.
(yao2024interactionofchikungunya pages 15-16)

A quantitative observation in primary macrophage infection reported a small, highly infected subset at 0.76% of macrophages at 24 h post infection. (yao2024interactionofchikungunya pages 1-2)

3.3 2024: SPC components in HCV assembly interactomes

A 2024 interaction-proteomics study of hepatitis C virus (HCV) assembly mapped host factors binding to viral structural proteins and noted that SPC components are engaged near these processes:
- SPC components co-precipitate with viral proteins, and SPCS3 was reported as part of the E2 accessory interactome.
- The authors state that SPC subunits SPCS1 and SPCS3 were previously recognized as important for flavivirus particle production and HCV.
- Reported transcript abundance values include SPCS3 ~12.01 RPKM (with SPCS2 ~34.69 RPKM) in their tabulated data.
(matthaei2024landscapeofproteinprotein pages 10-11, matthaei2024landscapeofproteinprotein pages 14-16)

3.4 2024: ER host-directed antiviral strategies target the same pathway SPCS3 participates in

A 2024 npj Viruses review synthesizes host-directed approaches targeting ER translocation and signal peptide processing (a pathway in which SPCS3 is structurally essential):
- The review notes that the SPC contains accessory subunits SPCS1–3 plus SEC11A/SEC11C and that SPCS1 and SPCS3 were identified as essential flavivirus host factors in genetic screens.
- It also lists potent inhibitors for translocation and signal peptidase cleavage (see Section 4).
(verhaegen2024theendoplasmicreticulum pages 4-5)

4) Current applications and real-world implementations

4.1 Host-directed antivirals targeting ER translocation/SPC-mediated processing

The ER translocation/SPC step is increasingly treated as a druggable host dependency for flaviviruses:
- Cotransin 8: active at 0.5 µM in Huh7 + C6/36 and 0.1–0.5 µM in monocyte-derived dendritic cells (MDDCs). (verhaegen2024theendoplasmicreticulum pages 7-8)
- PS3061: active at 1 µM in Huh7 + C6/36. (verhaegen2024theendoplasmicreticulum pages 7-8)
- Apratoxin S4: IC50 0.003 µM for DENV2 in Huh7.5 (table also indicates high selectivity index >300). (verhaegen2024theendoplasmicreticulum pages 7-8)
- Cavinafungin (signal peptidase inhibitor): reported DENV serotype IC50s in the 0.003–0.005 µM range (see statistics below). (verhaegen2024theendoplasmicreticulum pages 7-8)

These represent real experimental implementations (cell-based antiviral assays, host-directed strategies) that exploit the same ER biogenesis machinery in which SPCS3 is a core structural component. (verhaegen2024theendoplasmicreticulum pages 4-5, verhaegen2024theendoplasmicreticulum pages 7-8)

4.2 Virology/innate immunity implementation: antiviral restriction in macrophages

SPCS3’s anti-CHIKV activity has been shown in human macrophage model systems, suggesting that ER biogenesis proteins can have “moonlighting” antiviral roles independent of canonical enzymology. This provides an implementable framework for studying host restriction mechanisms and potentially designing viral attenuation strategies based on glycoprotein–host factor interaction surfaces. (yao2024interactionofchikungunya pages 15-16)

4.3 Protein quality control implementation

The 2023 quality-control model proposes SPC-mediated cleavage as a surveillance mechanism for misfolded/misassembled membrane proteins, cooperating with ERAD. Although not yet a clinical implementation, it is a concrete experimental paradigm (substrate discovery + cleavage validation + ER stress phenotyping) that can be used to functionally annotate SPCS3 in membrane proteostasis contexts. (zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60)

5) Expert opinions and analysis (authoritative synthesis)

5.1 Consensus mechanistic view (structural biology)

The structural interpretation is that SPC specificity is not primarily encoded by a large substrate-recognition surface on a single subunit, but by membrane shaping and the formation of a shared “TM window” that restricts which hydrophobic segments can access the active site. In this framework, SPCS3 is central because it helps form the inner lining of that window and stabilizes catalytic geometry through its luminal domain. (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12)

5.2 Emerging view (2023): dynamic roles of accessory subunits and expanded substrate space

The 2023 work argues the SPC may dynamically incorporate accessory elements to expand substrate range (canonical SPs vs cryptic TMD sites). Under this model, SPCS3 remains part of the catalytic core while SPCS1 provides a “recruitment/exosite” mechanism for challenging substrates that would otherwise be excluded by membrane thinning. (zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60)

5.3 Implication for annotation

A functional annotation for human SPCS3 should therefore emphasize:
- ER membrane SPC subunit essential for catalytic competence (structural stabilization of SEC11).
- Contribution to TM-window architecture controlling substrate selectivity.
- Participation in broader ER pathways (viral polyprotein processing dependencies; potential post-translocational quality-control cleavage contexts).
(liaci2021structureofthe pages 8-10, liaci2021structureofthe pages 10-12, verhaegen2024theendoplasmicreticulum pages 4-5)

6) Key statistics and quantitative data (recent and/or mechanistically defining)

Membrane thinning induced by SPC TM window: ~26% (simulation result). (liaci2021structureofthe pages 5-7)
TM window width: ~15 Å. (liaci2021structureofthe pages 1-3)
Signal peptide h-region length: mean ~11 residues; SPC generally cannot cleave SPs with h-regions >18–20 aa. (liaci2021structureofthe pages 10-12)
SPCS3 luminal glycosylation: Asp141 site ~98% glycosylated in HEK293 sample described. (liaci2021structureofthe pages 3-4)
CHIKV infection heterogeneity: 0.76% of primary macrophages reported as highly infected at 24 hpi (study-specific). (yao2024interactionofchikungunya pages 1-2)
HCV dataset expression metric: SPCS3 transcript abundance reported as ~12.01 RPKM (with SPCS2 ~34.69 RPKM) in the study’s table. (matthaei2024landscapeofproteinprotein pages 14-16)
Host-directed antiviral potencies (DENV; 2024 review table):
Cavinafungin IC50: 0.004 µM (DENV1), 0.005 µM (DENV2), 0.003 µM (DENV3), 0.003 µM (DENV4). (verhaegen2024theendoplasmicreticulum pages 7-8)
Apratoxin S4 IC50: 0.003 µM (DENV2; Huh7.5). (verhaegen2024theendoplasmicreticulum pages 7-8)
Cotransin 8: active at 0.5 µM (Huh7 + C6/36) and 0.1–0.5 µM (MDDCs). (verhaegen2024theendoplasmicreticulum pages 7-8)

7) Embedded evidence summary table

The following table consolidates identity, mechanistic function, recent (2023–2024) research, applications, and quantitative evidence.

Topic	Summary	Quantitative data	Best citation IDs
Identity / verified target	SPCS3 in human corresponds to signal peptidase complex subunit 3, also called SPC22/23; it is an accessory/non-proteolytic SPC subunit present in both human SPC paralogs with SEC11A or SEC11C.	Human SPC resolved as ~84 kDa hetero-tetrameric complex; two paralogs: SPC-A and SPC-C.	(liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4)
Core function in SPC	SPCS3 forms part of the functional core of the ER signal peptidase complex, supporting cleavage of N-terminal signal peptides from secretory and membrane protein precursors by stabilizing and positioning the SEC11 catalytic center rather than acting as the catalytic serine protease itself.	Human secretome/translocome estimate discussed as >3,000 signal peptides requiring SPC processing.	(liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 8-10, zanotti2023characterisationofthe pages 53-57)
Localization / topology	ER-resident membrane complex; SPCS3 has a luminal beta-sandwich (ASF1-like) domain that embraces SEC11 and TM helices that contribute to the SPC transmembrane window at the luminal membrane interface.	SPCS3 is highly N-glycosylated at Asp141 (~98%) in the HEK293-derived sample described.	(liaci2021structureofthe pages 3-4, liaci2021structureofthe pages 10-12)
Mechanistic insight: TM window and membrane thinning	All SPC subunits collectively form a lipid-filled TM window; inner lining includes essential subunits SEC11A/C and SPCS3. Local ER bilayer thinning near the active site acts as a physical selector for signal peptides.	Average local membrane thinning in simulations: ~26%; TM window width: ~15 Å.	(liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 5-7, liaci2021structureofthe pages 10-12)
Mechanistic insight: signal peptide selectivity	SPC specificity is explained by a molecular-ruler mechanism: short signal-peptide h-regions can enter the thinned TM window and access the c-region pocket, whereas longer TM helices are excluded.	Mean SP h-region length: 11 residues; SPC generally cannot cleave h-regions >18–20 aa.	(liaci2021structureofthe pages 5-7, liaci2021structureofthe pages 10-12)
2023 advance: membrane-protein quality control model	A 2023 characterization proposed that SPC also performs noncanonical, post-translocational quality-control cleavage of multipass membrane proteins with exposed cryptic sites. In this model, SPCS1 is the key recruitment or exosite factor, while SEC11A/C + SPCS3 form the catalytic core.	Proteome-wide prediction of ~1,500 membrane proteins with cryptic SPC cleavage sites; validated substrates included connexins, iRhom2, and Hrd1.	(zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60, zanotti2023characterisationofthe pages 1-8)
2024 finding: CHIKV interaction / host restriction	In human macrophage models, SPCS3 was identified as a CHIKV E1-binding host factor with anti-CHIKV activity; overexpression did not alter CHIKV poly-glycoprotein cleavage, implying a peptidase-independent antiviral role. E1 residue V220 helps the virus evade SPCS3 and eIF3k restriction.	Highly infected primary macrophage subset reported at 0.76% at 24 h.p.i.; siRNA comparisons involving SPCS3 reached p < 0.0001 in knockdown validation context.	(yao2024interactionofchikungunya pages 15-16, yao2024interactionofchikungunya pages 28-31, yao2024interactionofchikungunya pages 1-2)
2024 finding: HCV and flavivirus interactomes	2024 HCV interactomics placed SPC components near viral envelope and assembly proteins; SPCS3 appeared in the E2 accessory interactome, while prior work cited in the paper linked SPCS1/SPCS3 to flavivirus and HCV particle production.	SPCS3 transcript abundance in the HCV study table: RPKM ~12.01; SPCS2: ~34.69; interactome statistics included n = 3–4 for normalized IBAQ boxplots.	(matthaei2024landscapeofproteinprotein pages 10-11, matthaei2024landscapeofproteinprotein pages 11-14, matthaei2024landscapeofproteinprotein pages 14-16)
Translational relevance: ER-targeted antivirals affecting SPC-dependent biology	Recent flavivirus review highlights host-directed inhibition of ER translocation and signal peptide processing as a practical application area; although not SPCS3-selective, these compounds exploit the same ER biogenesis pathway in which SPCS3 functions.	Cavinafungin IC50s: 0.004 µM (DENV1), 0.005 µM (DENV2), 0.003 µM (DENV3), 0.003 µM (DENV4); Apratoxin S4: 0.003 µM (DENV2, Huh7.5); Cotransin 8 active at 0.5 µM (Huh7 + C6/36) and 0.1–0.5 µM (MDDCs); PS3061 active at 1 µM.	(verhaegen2024theendoplasmicreticulum pages 4-5, verhaegen2024theendoplasmicreticulum pages 7-8, verhaegen2024theendoplasmicreticulum pages 6-7)

Table: This table condenses the most important validated information about human SPCS3/SPC22/23, including identity, ER localization, signal peptidase mechanism, recent 2023-2024 functional findings, and quantitative values relevant to annotation and translational interpretation.

8) Visual evidence (structural localization of SPCS3 within SPC)

Cropped figure panels from Liaci et al. show SPC22/23 (SPCS3) positioned adjacent to SEC11 within the luminal body and the membrane-thinning “TM window” model used to explain signal peptide selectivity. (liaci2021structureofthe media 95c0a474, liaci2021structureofthe media d2d5d0ad)

9) References with URLs and publication dates (from retrieved sources)

Liaci AM et al. Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage. 2021-01. https://doi.org/10.2139/ssrn.3778304 (liaci2021structureofthe pages 1-3)
Zanotti A. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. 2023-01. https://doi.org/10.11588/heidok.00033417 (zanotti2023characterisationofthe pages 53-57)
Yao Z et al. Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production. 2024-09. https://doi.org/10.1038/s44318-024-00193-3 (yao2024interactionofchikungunya pages 1-2)
Matthaei A et al. Landscape of protein-protein interactions during hepatitis C virus assembly and release. 2024-02. https://doi.org/10.1128/spectrum.02562-22 (matthaei2024landscapeofproteinprotein pages 10-11)
Verhaegen M, Vermeire K. The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions. 2024-06. https://doi.org/10.1038/s44298-024-00031-7 (verhaegen2024theendoplasmicreticulum pages 4-5)

References

(liaci2021structureofthe pages 1-3): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe pages 3-4): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(zanotti2023characterisationofthe pages 53-57): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(liaci2021structureofthe pages 8-10): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe pages 10-12): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe pages 5-7): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(zanotti2023characterisationofthe pages 57-60): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(zanotti2023characterisationofthe pages 1-8): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(yao2024interactionofchikungunya pages 15-16): Zhenlan Yao, Sangeetha Ramachandran, Serina Huang, Erin Kim, Yasaman Jami-Alahmadi, Prashant Kaushal, Mehdi Bouhaddou, James A Wohlschlegel, and Melody MH Li. Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production. The EMBO Journal, 43:4625-4655, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00193-3, doi:10.1038/s44318-024-00193-3. This article has 6 citations.
(yao2024interactionofchikungunya pages 1-2): Zhenlan Yao, Sangeetha Ramachandran, Serina Huang, Erin Kim, Yasaman Jami-Alahmadi, Prashant Kaushal, Mehdi Bouhaddou, James A Wohlschlegel, and Melody MH Li. Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production. The EMBO Journal, 43:4625-4655, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00193-3, doi:10.1038/s44318-024-00193-3. This article has 6 citations.
(matthaei2024landscapeofproteinprotein pages 10-11): Alina Matthaei, Sebastian Joecks, Annika Frauenstein, Janina Bruening, Dorothea Bankwitz, Martina Friesland, Gisa Gerold, Gabrielle Vieyres, Lars Kaderali, Felix Meissner, and Thomas Pietschmann. Landscape of protein-protein interactions during hepatitis c virus assembly and release. Feb 2024. URL: https://doi.org/10.1128/spectrum.02562-22, doi:10.1128/spectrum.02562-22. This article has 9 citations and is from a domain leading peer-reviewed journal.
(matthaei2024landscapeofproteinprotein pages 14-16): Alina Matthaei, Sebastian Joecks, Annika Frauenstein, Janina Bruening, Dorothea Bankwitz, Martina Friesland, Gisa Gerold, Gabrielle Vieyres, Lars Kaderali, Felix Meissner, and Thomas Pietschmann. Landscape of protein-protein interactions during hepatitis c virus assembly and release. Feb 2024. URL: https://doi.org/10.1128/spectrum.02562-22, doi:10.1128/spectrum.02562-22. This article has 9 citations and is from a domain leading peer-reviewed journal.
(verhaegen2024theendoplasmicreticulum pages 4-5): Marijke Verhaegen and Kurt Vermeire. The endoplasmic reticulum (er): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions. npj Viruses, Jun 2024. URL: https://doi.org/10.1038/s44298-024-00031-7, doi:10.1038/s44298-024-00031-7. This article has 37 citations.
(verhaegen2024theendoplasmicreticulum pages 7-8): Marijke Verhaegen and Kurt Vermeire. The endoplasmic reticulum (er): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions. npj Viruses, Jun 2024. URL: https://doi.org/10.1038/s44298-024-00031-7, doi:10.1038/s44298-024-00031-7. This article has 37 citations.
(yao2024interactionofchikungunya pages 28-31): Zhenlan Yao, Sangeetha Ramachandran, Serina Huang, Erin Kim, Yasaman Jami-Alahmadi, Prashant Kaushal, Mehdi Bouhaddou, James A Wohlschlegel, and Melody MH Li. Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production. The EMBO Journal, 43:4625-4655, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00193-3, doi:10.1038/s44318-024-00193-3. This article has 6 citations.
(matthaei2024landscapeofproteinprotein pages 11-14): Alina Matthaei, Sebastian Joecks, Annika Frauenstein, Janina Bruening, Dorothea Bankwitz, Martina Friesland, Gisa Gerold, Gabrielle Vieyres, Lars Kaderali, Felix Meissner, and Thomas Pietschmann. Landscape of protein-protein interactions during hepatitis c virus assembly and release. Feb 2024. URL: https://doi.org/10.1128/spectrum.02562-22, doi:10.1128/spectrum.02562-22. This article has 9 citations and is from a domain leading peer-reviewed journal.
(verhaegen2024theendoplasmicreticulum pages 6-7): Marijke Verhaegen and Kurt Vermeire. The endoplasmic reticulum (er): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions. npj Viruses, Jun 2024. URL: https://doi.org/10.1038/s44298-024-00031-7, doi:10.1038/s44298-024-00031-7. This article has 37 citations.
(liaci2021structureofthe media 95c0a474): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe media d2d5d0ad): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.

Artifacts

Edison artifact artifact-00

Citations

liaci2021structureofthe pages 3-4
liaci2021structureofthe pages 5-7
liaci2021structureofthe pages 10-12
yao2024interactionofchikungunya pages 15-16
yao2024interactionofchikungunya pages 1-2
verhaegen2024theendoplasmicreticulum pages 4-5
verhaegen2024theendoplasmicreticulum pages 7-8
liaci2021structureofthe pages 1-3
matthaei2024landscapeofproteinprotein pages 14-16
zanotti2023characterisationofthe pages 53-57
matthaei2024landscapeofproteinprotein pages 10-11
liaci2021structureofthe pages 8-10
zanotti2023characterisationofthe pages 57-60
zanotti2023characterisationofthe pages 1-8
yao2024interactionofchikungunya pages 28-31
matthaei2024landscapeofproteinprotein pages 11-14
verhaegen2024theendoplasmicreticulum pages 6-7
https://doi.org/10.2139/ssrn.3778304
https://doi.org/10.11588/heidok.00033417
https://doi.org/10.1038/s44318-024-00193-3
https://doi.org/10.1128/spectrum.02562-22
https://doi.org/10.1038/s44298-024-00031-7
https://doi.org/10.2139/ssrn.3778304,
https://doi.org/10.11588/heidok.00033417,
https://doi.org/10.1038/s44318-024-00193-3,
https://doi.org/10.1128/spectrum.02562-22,
https://doi.org/10.1038/s44298-024-00031-7,

📚 Additional Documentation

Notes

(SPCS3-notes.md)

SPCS3 (Signal peptidase complex subunit 3) — review notes

UniProt: P61009 (SPCS3_HUMAN), 180 aa; aka SPC22/23, "Microsomal signal peptidase 22/23 kDa subunit". HGNC. Single-pass type II ER membrane protein (TM 12-32), large C-terminal lumenal domain (33-180). N-glycosylated in vivo.

Core identity / function

One of three non-catalytic accessory subunits (SPCS1, SPCS2, SPCS3) of the ER signal peptidase complex. Catalytic = SEC11A / SEC11C.
UniProt FUNCTION: "Essential component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum (PubMed:27499293, PubMed:34388369). Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface (By similarity)." [UniProt P61009]
Note: of the three accessory subunits, SPCS3 is described as ESSENTIAL for SPC catalytic activity (vs SPCS1 dispensable, SPCS2 enhancing). Still NOT itself the catalytic subunit — catalysis is in SEC11. It contributes a large lumenal domain and is thought to stabilize/position the active center.
UniProt SUBUNIT: "Component of the signal peptidase complex paralog A (SPC-A) ... Within the complex, interacts with SEC11A or SEC11C and SPCS1."
Cryo-EM: PMID:34388369 identifies SPCS3 in both SPC paralogs (PDB 7P2P/7P2Q).
PMID:27499293 (proteolysis IDA): study of regulated alternative translocation of TM4SF20 and CREB3L1 cleavage. Full text not in cache (abstract-only). It is cited by UniProt as experimental FUNCTION support and assigned SPCS3 an IDA "proteolysis" (GO:0006508) annotation by UniProt. Per guidelines, do not REMOVE an experimental IDA from full text we cannot see; treat as supporting the SPC proteolytic role.

Secondary / non-core

GO:0019082 viral protein processing (IMP, PMID:27383988): flavivirus host-factor role — "Plays an important role in virion production of flaviviruses such as West Nile virus, Japanese enchephalitis virus, Dengue virus type 2 and Yellow Fever virus." Real experimental phenotype; secondary.
Numerous bare protein binding IPI entries: intra-complex (SEC11A P67812, SEC11C Q9BY50, SPCS1 Q9Y6A9, SPCS2 Q15005) plus high-throughput interactome captures with disease/aggregation-prone proteins ATXN1 (P54253), HTT (P42858). All bare protein binding -> KEEP_AS_NON_CORE.

Annotation assessment

GO:0005787 signal peptidase complex (IBA, IEA, IPI/ComplexPortal) — CORE, ACCEPT.
GO:0005789 ER membrane (IEA, IDA, ISS, TAS) — CORE localization, ACCEPT.
GO:0005783 endoplasmic reticulum (IEA ARBA; IDA LIFEdb) — correct but less specific than ER membrane; ACCEPT (IDA fusion-protein localization) / the IEA ARBA also ACCEPT. Keep as supporting localization.
GO:0016020 membrane (IEA) — generic; KEEP_AS_NON_CORE.
GO:0045047 protein targeting to ER (IBA) — mis-specified; MODIFY -> GO:0006465 signal peptide processing.
GO:0016485 protein processing (IDA, ComplexPortal) — ACCEPT; core process (GO:0006465 more specific).
GO:0006508 proteolysis (IDA, PMID:27499293) — general parent of signal peptide cleavage; SPCS3 essential for SPC catalytic activity but not itself catalytic. ACCEPT as supporting the proteolytic role (experimental IDA; don't downgrade an experimental annotation), but note it's a general term; keep as non-core relative to the specific signal peptide processing. Use KEEP_AS_NON_CORE (general term, redundant with protein processing/signal peptide processing).
GO:0019082 viral protein processing (IMP, PMID:27383988) — viral host-factor; KEEP_AS_NON_CORE.
GO:0005515 protein binding (many IPI) — KEEP_AS_NON_CORE (bare protein binding).

Core function summary

Essential non-catalytic accessory subunit of the ER signal peptidase complex; single-pass type II ER membrane protein with a large lumenal domain that stabilizes/positions the catalytic center, required for SPC activity in signal peptide processing of preproteins. Secondary flavivirus host-factor role in viral protein processing/virion production.

Falcon deep-research findings (incorporated 2026-06)

New, notable: SPCS3 is an antiviral restriction factor against chikungunya virus (CHIKV), an alphavirus distinct from the previously documented flaviviral host-factor role. In human macrophages, SPCS3 was identified as a CHIKV E1 glycoprotein-binding protein with anti-CHIKV activity PMID:39261662. The positively selected E1 residue V220 is required for virion production and its mutation attenuates E1 binding to the restriction factors SPCS3 and eIF3k PMID:39261662. Falcon reports this anti-CHIKV activity is peptidase-independent (SPCS3 overexpression did not alter CHIKV polyglycoprotein cleavage) - i.e. a possible moonlighting function. (Verified PubMed; not cached.)
HCV assembly interactome: SPCS3 appears in the HCV E2 accessory interactome, and the authors note SPCS1/SPCS3 were previously recognized as important for flavivirus particle production and HCV PMID:38230952. Reinforces the secondary viral host-factor role already captured (flavivirus IMP, PMID:27383988). (Verified PubMed; not cached.)
Falcon's structural synthesis (Liaci 2021 = PMID:34388369, already cited) details SPCS3-specific architecture: a luminal beta-sandwich (ASF1-like) domain that "embraces" SEC11 and stabilizes the Ser-His-Asp catalytic triad, plus TM helices forming the inner lining of the membrane-thinning "TM window" (~26% thinning; ~15 A window). SPCS3 also reported highly N-glycosylated (Asn~141). Consistent with existing "essential for SPC catalytic activity by stabilizing/positioning the active center"; no new reference needed.
The "SPC quality-control" framing (SEC11A/C + SPCS3 as the catalytic core; SPCS1 as recruitment/exosite for cryptic noncanonical sites; ~1500 candidate substrates) derives from Zanotti 2023, a PhD thesis (doi:10.11588/heidok.00033417, no PMID, not peer-reviewed primary literature). Not added as a reference (unverifiable as PMID); logged here only.
Background reviews (Verhaegen & Vermeire 2024 npj Viruses) note SPCS1 and SPCS3 identified as essential flavivirus host factors and list ER-targeted antiviral inhibitors (cavinafungin, cotransins, apratoxins); background only, no gene-specific SPCS3 finding beyond what is captured. Not added.

Pn Notes

(SPCS3-pn-notes.md)

SPCS3 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P61009
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/SPCS3/SPCS3-ai-review.yaml
AIGR review HTML: missing - genes/human/SPCS3/SPCS3-ai-review.html
Gene notes: present - genes/human/SPCS3/SPCS3-notes.md
GOA TSV: present - genes/human/SPCS3/SPCS3-goa.tsv
UniProt record: present - genes/human/SPCS3/SPCS3-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/SPCS3.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/SPCS3.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/SPCS3/SPCS3-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 12; KEEP_AS_NON_CORE: 9; MODIFY: 1

PN Consistency Summary

Consistency: Deep research (notes + falcon) ↔ review YAML ↔ PN annotation are consistent. All four describe SPCS3 as a non-catalytic accessory subunit of the ER signal peptidase complex (SPC-A/SPC-C), essential for SEC11 catalytic activity, single-pass type II ER membrane protein, plus a secondary flavivirus host-factor role. No contradictions. The PN "ER signal peptidase" group→GO:0005787 matches the review's CORE annotation exactly.
PN story / NEW pressure: The PN group mapping (signal peptidase complex, GO:0005787) is already a CORE GOA/review annotation — already captured, no NEW pressure. The review's preferred process term GO:0006465 signal peptide processing (proposed replacement for the IBA GO:0045047) is already a standard term, also no NEW term needed.
Evidence alignment: Strong overlap. PN reference titles (cryo-EM SPC structure; flavivirus CRISPR screen) match review PMID:34388369 and PMID:27383988. Review adds breadth (CHIKV PMID:39261662, HCV PMID:38230952, ComplexPortal/Reactome) beyond the PN row.
Verdict: Internally consistent and well-curated. Recommend NOT propagating the class-level GO:0015031 protein transport to SPCS3 (over-reach); GO:0005787 is correctly captured.

Full Consistency Review

UniProt: P61009 · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE
PN placement: ER proteostasis|Protein transport|ER signal peptidase ; PN-node mapping: group=mapped/ok_for_propagation_to_go GO:0005787 signal peptidase complex; parent class "Protein transport"=mapped/ok GO:0015031 protein transport; branch=no_mapping.
Consistency: Deep research (notes + falcon) ↔ review YAML ↔ PN annotation are consistent. All four describe SPCS3 as a non-catalytic accessory subunit of the ER signal peptidase complex (SPC-A/SPC-C), essential for SEC11 catalytic activity, single-pass type II ER membrane protein, plus a secondary flavivirus host-factor role. No contradictions. The PN "ER signal peptidase" group→GO:0005787 matches the review's CORE annotation exactly.
PN story / NEW pressure: The PN group mapping (signal peptidase complex, GO:0005787) is already a CORE GOA/review annotation — already captured, no NEW pressure. The review's preferred process term GO:0006465 signal peptide processing (proposed replacement for the IBA GO:0045047) is already a standard term, also no NEW term needed.
Mapping strategy: Concern — the parent class node "ER proteostasis|Protein transport" projects GO:0015031 protein transport as new_to_goa to SPCS3. SPCS3 does NOT mediate protein transport; it is a signal peptidase accessory subunit acting downstream of translocation (the review explicitly MODIFIES the IBA "protein targeting to ER" to "signal peptide processing"). GO:0015031 over-reaches here, analogous to the TOMM20/HSPA8/RAB7A "broader" rejections. The group-level GO:0005787 mapping is correct; the class-level GO:0015031 projection should not be propagated to SPCS3.
Evidence alignment: Strong overlap. PN reference titles (cryo-EM SPC structure; flavivirus CRISPR screen) match review PMID:34388369 and PMID:27383988. Review adds breadth (CHIKV PMID:39261662, HCV PMID:38230952, ComplexPortal/Reactome) beyond the PN row.
Verdict: Internally consistent and well-curated. Recommend NOT propagating the class-level GO:0015031 protein transport to SPCS3 (over-reach); GO:0005787 is correctly captured.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/SPCS3/SPCS3-ai-review.yaml
PN workbook rows: 1

PN row 1: ER proteostasis | Protein transport | ER signal peptidase

UniProt: P61009
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Protein transport|ER signal peptidase
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0005787 signal peptidase complex]
  rationale: This PN group denotes ER signal peptidase complex components. The matching GO cellular-component term is the direct propagation target.
- [class] ER proteostasis|Protein transport
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
  rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
- [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.

Projected GO annotations (2)

GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport
GO:0005787 signal peptidase complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Protein transport|ER signal peptidase

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: 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.

SPCS3

Gene Description

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human SPCS3 (UniProt P61009) — Functional Annotation

0) Target identity verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 Signal peptides and signal peptidase complex (SPC)

1.2 What SPCS3 is (and is not)

2) Molecular function, biochemical role, and mechanism

2.1 SPC composition and where SPCS3 fits

2.2 Cellular localization and topology

2.3 Catalysis (what reaction is carried out?)

2.4 Substrate specificity: “TM window” and membrane thinning

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2023: SPC as a membrane-protein quality-control protease (noncanonical substrates)

3.2 2024: SPCS3 as an antiviral restriction factor for chikungunya virus (CHIKV)

3.3 2024: SPC components in HCV assembly interactomes

3.4 2024: ER host-directed antiviral strategies target the same pathway SPCS3 participates in

4) Current applications and real-world implementations

4.1 Host-directed antivirals targeting ER translocation/SPC-mediated processing

4.2 Virology/innate immunity implementation: antiviral restriction in macrophages

4.3 Protein quality control implementation

5) Expert opinions and analysis (authoritative synthesis)

5.1 Consensus mechanistic view (structural biology)

5.2 Emerging view (2023): dynamic roles of accessory subunits and expanded substrate space

5.3 Implication for annotation

6) Key statistics and quantitative data (recent and/or mechanistically defining)

7) Embedded evidence summary table

8) Visual evidence (structural localization of SPCS3 within SPC)

9) References with URLs and publication dates (from retrieved sources)

Artifacts

Citations

📚 Additional Documentation

Notes

SPCS3 (Signal peptidase complex subunit 3) — review notes

Core identity / function

Secondary / non-core

Annotation assessment

Core function summary

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

SPCS3 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Protein transport | ER signal peptidase

Projected GO annotations (2)

Note

📄 View Raw YAML