{"gene":"SPCS3","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":1997,"finding":"Yeast Spc3p (homolog of mammalian SPC22/23, i.e., SPCS3) is an essential subunit of the signal peptidase complex in the endoplasmic reticulum; depletion of SPC3 leads to accumulation of secretory protein precursors in vivo and loss of signal peptidase activity in vitro, demonstrating it is required for signal peptide cleavage.","method":"Genetic depletion (SPC3 knockout/depletion in yeast), in vivo precursor accumulation assay, in vitro signal peptidase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent labs published simultaneously using in vitro enzymatic assay plus in vivo genetic depletion, replicated across both papers (PMIDs 9148930 and 9148931)","pmids":["9148930","9148931"],"is_preprint":false},{"year":1997,"finding":"Spc3p (SPCS3 yeast ortholog) is an essential component of the four-subunit yeast signal peptidase complex alongside Sec11p, Spc1p, and Spc2p; unlike the non-essential Spc1p and Spc2p, Spc3p (like Sec11p) is required for cell viability, indicating that eukaryotic signal peptidase requires a second essential catalytic/structural subunit beyond the catalytic Sec11p.","method":"Protein purification of Spc3p, genetic complementation, in vitro signal peptidase reconstitution","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — protein purified and characterized, activity confirmed in vitro, replicated by independent lab in same year","pmids":["9148931","9148930"],"is_preprint":false},{"year":2010,"finding":"Mouse Spcs3 is the parental gene from which the retrotransposed paralogs Arxes1 and Arxes2 arose; unlike the Arxes paralogs, Spcs3 itself is dispensable for adipogenesis, establishing a functional divergence between Spcs3 and its retrotransposed copies.","method":"RNA interference knockdown in adipocyte cell models, gene expression analysis, retrotransposition/phylogenetic analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined adipogenesis phenotype readout, but Spcs3 dispensability finding is from a single lab","pmids":["21177646"],"is_preprint":false},{"year":2024,"finding":"SPCS3 binds chikungunya virus (CHIKV) glycoprotein E1 and acts as a host restriction factor limiting virion production in macrophages; mutation of E1 residue V220 (positively selected) attenuates E1 interaction with SPCS3, and SPCS3 associates with eIF3k in the cytoplasm during infection.","method":"Proteomic interaction analysis (Co-IP/MS), functional validation with viral chimeras and point mutants, evolutionary selection analysis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic interaction plus functional validation with mutants in a single lab; mechanistic pathway placement supported by multiple orthogonal approaches","pmids":["39261662"],"is_preprint":false}],"current_model":"SPCS3 (SPC22/23) is an essential subunit of the endoplasmic reticulum signal peptidase complex required for signal peptide cleavage and cell viability, functioning as a second indispensable non-catalytic subunit alongside the catalytic SEC11/Sec11p; additionally, SPCS3 acts as a host restriction factor against chikungunya virus by binding viral glycoprotein E1 and limiting virion production in macrophages."},"narrative":{"mechanistic_narrative":"SPCS3 (SPC22/23) is an essential, non-catalytic subunit of the endoplasmic reticulum signal peptidase complex required for the cleavage of signal peptides from secretory protein precursors [PMID:9148930, PMID:9148931]. In the yeast complex, the SPCS3 ortholog Spc3p assembles with the catalytic Sec11p and the non-essential Spc1p and Spc2p; unlike the latter two, Spc3p is indispensable for cell viability and for signal peptidase activity, establishing it as a second essential subunit beyond the catalytic core [PMID:9148931, PMID:9148930]. Depletion of the gene causes accumulation of uncleaved secretory precursors in vivo and abolishes signal peptidase activity in vitro [PMID:9148930, PMID:9148931]. Independent of its housekeeping role in protein maturation, SPCS3 acts as a host restriction factor against chikungunya virus, binding the viral glycoprotein E1 to limit virion production in macrophages; the positively selected E1 residue V220 mediates this interaction, and SPCS3 associates with eIF3k in the cytoplasm during infection [PMID:39261662]. The mouse gene is the parent of the retrotransposed paralogs Arxes1 and Arxes2, and unlike those copies is dispensable for adipogenesis [PMID:21177646].","teleology":[{"year":1997,"claim":"Established that SPCS3's ortholog is not merely an accessory factor but is functionally required for signal peptide cleavage, answering whether the catalytic Sec11p suffices for signal peptidase activity.","evidence":"Genetic depletion of SPC3 in yeast with in vivo precursor accumulation assay and in vitro signal peptidase activity assay; independent purification, complementation and reconstitution of the four-subunit complex","pmids":["9148930","9148931"],"confidence":"High","gaps":["Does not resolve the structural basis by which SPCS3 contributes to catalysis or substrate presentation","Mammalian SPCS3 function inferred from yeast Spc3p rather than directly tested in the 1997 work","Whether SPCS3 has activities outside the signal peptidase complex was not addressed"]},{"year":2010,"claim":"Distinguished SPCS3 from its retrotransposed paralogs by showing the parent gene is dispensable for adipogenesis, defining a functional divergence between Spcs3 and Arxes1/Arxes2.","evidence":"RNAi knockdown in adipocyte cell models with gene expression readouts and retrotransposition/phylogenetic analysis","pmids":["21177646"],"confidence":"Medium","gaps":["Single-lab dispensability finding without genetic knockout confirmation","Does not address whether SPCS3 contributes to other differentiation programs","Mechanistic basis of paralog functional divergence not defined"]},{"year":2024,"claim":"Revealed a non-canonical antiviral role: SPCS3 restricts chikungunya virus by directly engaging the viral E1 glycoprotein, identifying a host-pathogen interface shaped by positive selection.","evidence":"Co-IP/MS proteomic interaction analysis, functional validation with viral chimeras and E1 point mutants, and evolutionary selection analysis in macrophages","pmids":["39261662"],"confidence":"Medium","gaps":["Single-lab finding; reciprocal validation and structural definition of the SPCS3–E1 interface not established","Functional role of the SPCS3–eIF3k cytoplasmic association during infection unresolved","Whether antiviral restriction depends on signal peptidase activity is not determined"]},{"year":null,"claim":"How SPCS3 mechanistically reconciles its essential role in signal peptide cleavage with its restriction of chikungunya virus, and whether the two functions share a structural or catalytic basis, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human SPCS3 within the signal peptidase complex in the corpus","Mechanism by which SPCS3 limits virion production is uncharacterized","Direct experimental characterization of mammalian SPCS3 catalytic contribution is absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["signal peptidase complex"],"partners":["SEC11","SPCS1","SPCS2","EIF3K"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61009","full_name":"Signal peptidase complex subunit 3","aliases":["Microsomal signal peptidase 22/23 kDa subunit","SPC22/23","SPase 22/23 kDa subunit"],"length_aa":180,"mass_kda":20.3,"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) (Microbial infection) 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","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P61009/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SPCS3","classification":"Common Essential","n_dependent_lines":1147,"n_total_lines":1208,"dependency_fraction":0.9495033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD46","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"CYB5R3","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"PGRMC2","stoichiometry":0.2},{"gene":"RAB6B","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"STK4","stoichiometry":0.2},{"gene":"TMEM147","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SPCS3","total_profiled":1310},"omim":[{"mim_id":"618854","title":"SIGNAL PEPTIDASE COMPLEX, SUBUNIT 3; SPCS3","url":"https://www.omim.org/entry/618854"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPCS3"},"hgnc":{"alias_symbol":["FLJ22649","SPC22/23","SPC3","YLR066W","PRO3567"],"prev_symbol":[]},"alphafold":{"accession":"P61009","domains":[{"cath_id":"2.60.40","chopping":"34-167","consensus_level":"high","plddt":91.9408,"start":34,"end":167},{"cath_id":"1.20.5","chopping":"1-30","consensus_level":"medium","plddt":93.0623,"start":1,"end":30}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61009","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61009-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61009-F1-predicted_aligned_error_v6.png","plddt_mean":91.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPCS3","jax_strain_url":"https://www.jax.org/strain/search?query=SPCS3"},"sequence":{"accession":"P61009","fasta_url":"https://rest.uniprot.org/uniprotkb/P61009.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61009/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61009"}},"corpus_meta":[{"pmid":"24480542","id":"PMC_24480542","title":"Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency.","date":"2014","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24480542","citation_count":78,"is_preprint":false},{"pmid":"9148930","id":"PMC_9148930","title":"In addition to SEC11, a newly identified gene, SPC3, is essential for signal peptidase activity in the yeast endoplasmic reticulum.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9148930","citation_count":41,"is_preprint":false},{"pmid":"9148931","id":"PMC_9148931","title":"The yeast SPC22/23 homolog Spc3p is essential for signal peptidase activity.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9148931","citation_count":40,"is_preprint":false},{"pmid":"21177646","id":"PMC_21177646","title":"Arxes: retrotransposed genes required for adipogenesis.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21177646","citation_count":16,"is_preprint":false},{"pmid":"20954177","id":"PMC_20954177","title":"Systems genetics analysis of mouse chondrocyte differentiation.","date":"2011","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/20954177","citation_count":12,"is_preprint":false},{"pmid":"33359122","id":"PMC_33359122","title":"Vitamin E can promote spermatogenesis by regulating the expression of proteins associated with the plasma membranes and protamine biosynthesis.","date":"2021","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/33359122","citation_count":8,"is_preprint":false},{"pmid":"39261662","id":"PMC_39261662","title":"Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39261662","citation_count":6,"is_preprint":false},{"pmid":"31695175","id":"PMC_31695175","title":"A multimodal attempt to follow-up linkage regions using RNA expression, SNPs and CpG methylation in schizophrenia and bipolar disorder kindreds.","date":"2019","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/31695175","citation_count":3,"is_preprint":false},{"pmid":"36982963","id":"PMC_36982963","title":"DNA Methylation Analysis Identifies Novel Epigenetic Loci in Dilated Murine Heart upon Exposure to Volume Overload.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36982963","citation_count":2,"is_preprint":false},{"pmid":"41726604","id":"PMC_41726604","title":"Two-Step Algorithmic Selection of Interspecies Sequence-Mismatch-Based Housekeeping Genes for Precise Gene-Expression Assessment in PBMC-Humanized NSG Mice.","date":"2026","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/41726604","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6646,"output_tokens":1107,"usd":0.018271,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7649,"output_tokens":1818,"usd":0.041848,"stage2_stop_reason":"end_turn"},"total_usd":0.060119,"stage1_batch_id":"msgbatch_0147LFpL5iCPFZF66xp23BqC","stage2_batch_id":"msgbatch_01Crtwc6eCsZh1CrnfJhY7J7","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Spc3p (homolog of mammalian SPC22/23, i.e., SPCS3) is an essential subunit of the signal peptidase complex in the endoplasmic reticulum; depletion of SPC3 leads to accumulation of secretory protein precursors in vivo and loss of signal peptidase activity in vitro, demonstrating it is required for signal peptide cleavage.\",\n      \"method\": \"Genetic depletion (SPC3 knockout/depletion in yeast), in vivo precursor accumulation assay, in vitro signal peptidase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent labs published simultaneously using in vitro enzymatic assay plus in vivo genetic depletion, replicated across both papers (PMIDs 9148930 and 9148931)\",\n      \"pmids\": [\"9148930\", \"9148931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Spc3p (SPCS3 yeast ortholog) is an essential component of the four-subunit yeast signal peptidase complex alongside Sec11p, Spc1p, and Spc2p; unlike the non-essential Spc1p and Spc2p, Spc3p (like Sec11p) is required for cell viability, indicating that eukaryotic signal peptidase requires a second essential catalytic/structural subunit beyond the catalytic Sec11p.\",\n      \"method\": \"Protein purification of Spc3p, genetic complementation, in vitro signal peptidase reconstitution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — protein purified and characterized, activity confirmed in vitro, replicated by independent lab in same year\",\n      \"pmids\": [\"9148931\", \"9148930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mouse Spcs3 is the parental gene from which the retrotransposed paralogs Arxes1 and Arxes2 arose; unlike the Arxes paralogs, Spcs3 itself is dispensable for adipogenesis, establishing a functional divergence between Spcs3 and its retrotransposed copies.\",\n      \"method\": \"RNA interference knockdown in adipocyte cell models, gene expression analysis, retrotransposition/phylogenetic analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined adipogenesis phenotype readout, but Spcs3 dispensability finding is from a single lab\",\n      \"pmids\": [\"21177646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPCS3 binds chikungunya virus (CHIKV) glycoprotein E1 and acts as a host restriction factor limiting virion production in macrophages; mutation of E1 residue V220 (positively selected) attenuates E1 interaction with SPCS3, and SPCS3 associates with eIF3k in the cytoplasm during infection.\",\n      \"method\": \"Proteomic interaction analysis (Co-IP/MS), functional validation with viral chimeras and point mutants, evolutionary selection analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic interaction plus functional validation with mutants in a single lab; mechanistic pathway placement supported by multiple orthogonal approaches\",\n      \"pmids\": [\"39261662\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPCS3 (SPC22/23) is an essential subunit of the endoplasmic reticulum signal peptidase complex required for signal peptide cleavage and cell viability, functioning as a second indispensable non-catalytic subunit alongside the catalytic SEC11/Sec11p; additionally, SPCS3 acts as a host restriction factor against chikungunya virus by binding viral glycoprotein E1 and limiting virion production in macrophages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPCS3 (SPC22/23) is an essential, non-catalytic subunit of the endoplasmic reticulum signal peptidase complex required for the cleavage of signal peptides from secretory protein precursors [#0]. In the yeast complex, the SPCS3 ortholog Spc3p assembles with the catalytic Sec11p and the non-essential Spc1p and Spc2p; unlike the latter two, Spc3p is indispensable for cell viability and for signal peptidase activity, establishing it as a second essential subunit beyond the catalytic core [#1]. Depletion of the gene causes accumulation of uncleaved secretory precursors in vivo and abolishes signal peptidase activity in vitro [#0]. Independent of its housekeeping role in protein maturation, SPCS3 acts as a host restriction factor against chikungunya virus, binding the viral glycoprotein E1 to limit virion production in macrophages; the positively selected E1 residue V220 mediates this interaction, and SPCS3 associates with eIF3k in the cytoplasm during infection [#3]. The mouse gene is the parent of the retrotransposed paralogs Arxes1 and Arxes2, and unlike those copies is dispensable for adipogenesis [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that SPCS3's ortholog is not merely an accessory factor but is functionally required for signal peptide cleavage, answering whether the catalytic Sec11p suffices for signal peptidase activity.\",\n      \"evidence\": \"Genetic depletion of SPC3 in yeast with in vivo precursor accumulation assay and in vitro signal peptidase activity assay; independent purification, complementation and reconstitution of the four-subunit complex\",\n      \"pmids\": [\"9148930\", \"9148931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve the structural basis by which SPCS3 contributes to catalysis or substrate presentation\",\n        \"Mammalian SPCS3 function inferred from yeast Spc3p rather than directly tested in the 1997 work\",\n        \"Whether SPCS3 has activities outside the signal peptidase complex was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Distinguished SPCS3 from its retrotransposed paralogs by showing the parent gene is dispensable for adipogenesis, defining a functional divergence between Spcs3 and Arxes1/Arxes2.\",\n      \"evidence\": \"RNAi knockdown in adipocyte cell models with gene expression readouts and retrotransposition/phylogenetic analysis\",\n      \"pmids\": [\"21177646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab dispensability finding without genetic knockout confirmation\",\n        \"Does not address whether SPCS3 contributes to other differentiation programs\",\n        \"Mechanistic basis of paralog functional divergence not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-canonical antiviral role: SPCS3 restricts chikungunya virus by directly engaging the viral E1 glycoprotein, identifying a host-pathogen interface shaped by positive selection.\",\n      \"evidence\": \"Co-IP/MS proteomic interaction analysis, functional validation with viral chimeras and E1 point mutants, and evolutionary selection analysis in macrophages\",\n      \"pmids\": [\"39261662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; reciprocal validation and structural definition of the SPCS3–E1 interface not established\",\n        \"Functional role of the SPCS3–eIF3k cytoplasmic association during infection unresolved\",\n        \"Whether antiviral restriction depends on signal peptidase activity is not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SPCS3 mechanistically reconciles its essential role in signal peptide cleavage with its restriction of chikungunya virus, and whether the two functions share a structural or catalytic basis, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of human SPCS3 within the signal peptidase complex in the corpus\",\n        \"Mechanism by which SPCS3 limits virion production is uncharacterized\",\n        \"Direct experimental characterization of mammalian SPCS3 catalytic contribution is absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"signal peptidase complex\"],\n    \"partners\": [\"SEC11\", \"SPCS1\", \"SPCS2\", \"eIF3k\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}