{"gene":"SPCS2","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":2024,"finding":"SPCS2 physically interacts with HCV assembly proteins p7 and E2 (as well as viral NS2), identified by affinity purification mass spectrometry of HCV-infected cells using epitope-tagged viral constructs.","method":"Affinity purification mass spectrometry (AP-MS) in HCV-infected cells","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — AP-MS with functional viral constructs, single lab, single method; interaction identified but not further validated by orthogonal method in this paper","pmids":["38230952"],"is_preprint":false},{"year":2026,"finding":"SPCS2 interacts with JEV non-structural proteins NS2B and NS5, identified by co-immunoprecipitation of JEV-infected cell lysates followed by mass spectrometry.","method":"Co-immunoprecipitation and mass spectrometry","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS identification, single lab, two orthogonal approaches (Co-IP + MS)","pmids":["41910145"],"is_preprint":false},{"year":2026,"finding":"SPCS2 is required for JEV replication: silencing and knockout of endogenous SPCS2 markedly impaired intracellular virion assembly and production of infectious JEV particles, without affecting viral attachment, cell entry, RNA replication, protein translation/processing, or formation of ER membrane-invaginated vesicles.","method":"siRNA silencing and CRISPR knockout with infectious particle production assays and mechanistic dissection of viral life cycle steps","journal":"Microbiology spectrum","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal functional readouts (virion assembly, particle production, RNA replication, cell entry) in single rigorous study ruling out alternative mechanisms","pmids":["41910145"],"is_preprint":false},{"year":2026,"finding":"SPCS2 depletion promotes degradation of JEV viral proteins prM, E, and NS1, but not NS2B, indicating SPCS2 functions to maintain stability of specific viral structural and non-structural proteins during infection.","method":"SPCS2 knockout followed by immunoblotting for viral protein levels","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with protein-level readout, single lab, selective effect across multiple viral proteins supports specificity","pmids":["41910145"],"is_preprint":false},{"year":2014,"finding":"SPCS2 pre-mRNA contains U12-type introns whose splicing depends on the minor spliceosome; mutations in the minor spliceosome component RNPC3 cause defective splicing of SPCS2 transcripts in patient cells, linking SPCS2 to minor spliceosome-dependent mRNA processing.","method":"Patient cell RNA analysis; U11/U12 di-snRNP formation assays; splicing assays in cells from individuals with RNPC3 mutations","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional splicing analysis in patient-derived cells, single study, but no direct SPCS2 protein functional follow-up","pmids":["24480542"],"is_preprint":false}],"current_model":"SPCS2 (signal peptidase complex subunit 2) is an endoplasmic reticulum-resident protein that physically interacts with viral non-structural proteins (JEV NS2B/NS5; HCV p7/E2/NS2) and acts as a critical host factor for flavivirus replication by maintaining the stability of viral structural and non-structural proteins (prM, E, NS1) and supporting intracellular virion assembly, without affecting viral entry, RNA replication, or ER membrane remodeling; its pre-mRNA is processed by the minor spliceosome via U12-type introns."},"narrative":{"mechanistic_narrative":"SPCS2 is an endoplasmic reticulum-associated host factor co-opted by flaviviruses and hepaciviruses to support viral particle production [PMID:41910145]. It physically engages viral proteins from distinct virus families, binding the JEV non-structural proteins NS2B and NS5 [PMID:41910145] and the HCV assembly proteins p7 and E2 along with NS2 [PMID:38230952]. In JEV infection, SPCS2 is specifically required for the intracellular assembly of infectious virions: its silencing or knockout abolishes infectious particle production while leaving viral attachment, cell entry, RNA replication, protein translation/processing, and ER membrane-invaginated vesicle formation intact [PMID:41910145]. Mechanistically, SPCS2 maintains the stability of selected viral proteins, since its depletion promotes degradation of the structural proteins prM and E and the non-structural protein NS1, but not NS2B [PMID:41910145]. At the level of its own expression, the SPCS2 pre-mRNA carries U12-type introns and is processed by the minor spliceosome [PMID:24480542]. Beyond these findings, no endogenous cellular substrate or non-viral physiological function of SPCS2 has been characterized in the available corpus.","teleology":[{"year":2014,"claim":"Established that SPCS2 expression depends on minor spliceosome processing, defining a layer of regulation over its own production.","evidence":"RNA splicing analysis in cells from individuals carrying RNPC3 mutations, with U11/U12 di-snRNP formation assays","pmids":["24480542"],"confidence":"Medium","gaps":["No follow-up on SPCS2 protein function or how reduced splicing translates to phenotype","Does not address the cellular role of the SPCS2 protein itself"]},{"year":2024,"claim":"Identified SPCS2 as a physical interactor of HCV assembly machinery, the first link between this host protein and viral particle formation.","evidence":"Affinity purification mass spectrometry in HCV-infected cells with epitope-tagged viral constructs","pmids":["38230952"],"confidence":"Medium","gaps":["Interaction not validated by an orthogonal method in this study","Functional consequence for HCV replication or assembly not tested","Direct vs. indirect binding not resolved"]},{"year":2026,"claim":"Extended the SPCS2-virus interaction to a second virus family and pinned down its functional role as an assembly factor, distinguishing it from entry and replication steps.","evidence":"Co-IP/MS identification of JEV NS2B and NS5 binding, combined with siRNA/CRISPR knockout and stepwise dissection of the JEV life cycle","pmids":["41910145"],"confidence":"High","gaps":["Molecular basis of how SPCS2 promotes virion assembly is unresolved","Whether NS2B/NS5 binding is required for the assembly function is untested"]},{"year":2026,"claim":"Provided a mechanistic basis for the assembly defect by showing SPCS2 selectively stabilizes specific viral proteins.","evidence":"Immunoblotting of viral protein levels in SPCS2 knockout JEV-infected cells","pmids":["41910145"],"confidence":"Medium","gaps":["Degradation pathway acting on prM/E/NS1 in SPCS2 absence not identified","Whether stabilization is direct or via a downstream chaperone/protease activity unknown"]},{"year":null,"claim":"The endogenous cellular function of SPCS2 and its normal substrates remain undefined; all functional data derive from viral hijacking contexts.","evidence":"No discovery in the corpus addresses a host physiological role independent of viral infection","pmids":[],"confidence":"Low","gaps":["No native cellular substrate or partner identified","Mechanism by which SPCS2 stabilizes proteins is uncharacterized","No structural model of SPCS2 or its viral-protein interfaces"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["NS2B","NS5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15005","full_name":"Signal peptidase complex subunit 2","aliases":["Microsomal signal peptidase 25 kDa subunit","SPase 25 kDa subunit"],"length_aa":226,"mass_kda":25.0,"function":"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:34388369). Enhances the enzymatic activity of SPC and facilitates the interactions between different components of the translocation site (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q15005/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SPCS2","classification":"Common Essential","n_dependent_lines":1123,"n_total_lines":1208,"dependency_fraction":0.929635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"STK4","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SPCS2","total_profiled":1310},"omim":[{"mim_id":"619411","title":"SIGNAL PEPTIDASE COMPLEX, SUBUNIT 2; SPCS2","url":"https://www.omim.org/entry/619411"},{"mim_id":"610358","title":"SIGNAL PEPTIDASE COMPLEX, SUBUNIT 1; SPCS1","url":"https://www.omim.org/entry/610358"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPCS2"},"hgnc":{"alias_symbol":["KIAA0102"],"prev_symbol":[]},"alphafold":{"accession":"Q15005","domains":[{"cath_id":"-","chopping":"49-134_153-224","consensus_level":"medium","plddt":73.9861,"start":49,"end":224}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15005","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15005-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15005-F1-predicted_aligned_error_v6.png","plddt_mean":64.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPCS2","jax_strain_url":"https://www.jax.org/strain/search?query=SPCS2"},"sequence":{"accession":"Q15005","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15005.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15005/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15005"}},"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":"31432149","id":"PMC_31432149","title":"Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma.","date":"2019","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31432149","citation_count":21,"is_preprint":false},{"pmid":"18355231","id":"PMC_18355231","title":"Biosynthesis of spectinomycin: heterologous production of spectinomycin and spectinamine in an aminoglycoside-deficient host, Streptomyces venezuelae YJ003.","date":"2008","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18355231","citation_count":14,"is_preprint":false},{"pmid":"33925480","id":"PMC_33925480","title":"NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33925480","citation_count":12,"is_preprint":false},{"pmid":"37895309","id":"PMC_37895309","title":"Genome-Wide Association Study of the Reproductive Traits of the Dazu Black Goat (Capra hircus) Using Whole-Genome Resequencing.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37895309","citation_count":11,"is_preprint":false},{"pmid":"38245436","id":"PMC_38245436","title":"SPCS, a Novel Classifier System Based on Senescence Axis Regulators Reveals Tumor Microenvironment Heterogeneity and Guides Frontline Therapy for Clear Cell Renal Carcinoma.","date":"2024","source":"Clinical genitourinary cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38245436","citation_count":8,"is_preprint":false},{"pmid":"38230952","id":"PMC_38230952","title":"Landscape of protein-protein interactions during hepatitis C virus assembly and release.","date":"2024","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/38230952","citation_count":5,"is_preprint":false},{"pmid":"24503209","id":"PMC_24503209","title":"Heterologous production of spectinomycin in Streptomyces venezuelae by exploiting the dTDP-D-desosamine pathway.","date":"2014","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/24503209","citation_count":5,"is_preprint":false},{"pmid":"35646058","id":"PMC_35646058","title":"Placental Gene Transcript Proportions are Altered in the Presence of In Utero Arsenic and Cadmium Exposures, Genetic Variants, and Birth Weight Differences.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35646058","citation_count":3,"is_preprint":false},{"pmid":"40432288","id":"PMC_40432288","title":"miR-486-5p Inhibits eNOS and Angiogenesis in Cultured Endothelial Cells by Targeting MAML3.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40432288","citation_count":1,"is_preprint":false},{"pmid":"41204409","id":"PMC_41204409","title":"Identification of gene modules associated with B cell activation and tissue remodeling in primary Sjögren's syndrome.","date":"2025","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41204409","citation_count":1,"is_preprint":false},{"pmid":"41910145","id":"PMC_41910145","title":"SPCS2 serves as a critical host factor for JEV replication by regulating viral protein stability and virion assembly.","date":"2026","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/41910145","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9248,"output_tokens":1162,"usd":0.022587,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7756,"output_tokens":1742,"usd":0.041165,"stage2_stop_reason":"end_turn"},"total_usd":0.063752,"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\": 2024,\n      \"finding\": \"SPCS2 physically interacts with HCV assembly proteins p7 and E2 (as well as viral NS2), identified by affinity purification mass spectrometry of HCV-infected cells using epitope-tagged viral constructs.\",\n      \"method\": \"Affinity purification mass spectrometry (AP-MS) in HCV-infected cells\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — AP-MS with functional viral constructs, single lab, single method; interaction identified but not further validated by orthogonal method in this paper\",\n      \"pmids\": [\"38230952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SPCS2 interacts with JEV non-structural proteins NS2B and NS5, identified by co-immunoprecipitation of JEV-infected cell lysates followed by mass spectrometry.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS identification, single lab, two orthogonal approaches (Co-IP + MS)\",\n      \"pmids\": [\"41910145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SPCS2 is required for JEV replication: silencing and knockout of endogenous SPCS2 markedly impaired intracellular virion assembly and production of infectious JEV particles, without affecting viral attachment, cell entry, RNA replication, protein translation/processing, or formation of ER membrane-invaginated vesicles.\",\n      \"method\": \"siRNA silencing and CRISPR knockout with infectious particle production assays and mechanistic dissection of viral life cycle steps\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal functional readouts (virion assembly, particle production, RNA replication, cell entry) in single rigorous study ruling out alternative mechanisms\",\n      \"pmids\": [\"41910145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SPCS2 depletion promotes degradation of JEV viral proteins prM, E, and NS1, but not NS2B, indicating SPCS2 functions to maintain stability of specific viral structural and non-structural proteins during infection.\",\n      \"method\": \"SPCS2 knockout followed by immunoblotting for viral protein levels\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with protein-level readout, single lab, selective effect across multiple viral proteins supports specificity\",\n      \"pmids\": [\"41910145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SPCS2 pre-mRNA contains U12-type introns whose splicing depends on the minor spliceosome; mutations in the minor spliceosome component RNPC3 cause defective splicing of SPCS2 transcripts in patient cells, linking SPCS2 to minor spliceosome-dependent mRNA processing.\",\n      \"method\": \"Patient cell RNA analysis; U11/U12 di-snRNP formation assays; splicing assays in cells from individuals with RNPC3 mutations\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional splicing analysis in patient-derived cells, single study, but no direct SPCS2 protein functional follow-up\",\n      \"pmids\": [\"24480542\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPCS2 (signal peptidase complex subunit 2) is an endoplasmic reticulum-resident protein that physically interacts with viral non-structural proteins (JEV NS2B/NS5; HCV p7/E2/NS2) and acts as a critical host factor for flavivirus replication by maintaining the stability of viral structural and non-structural proteins (prM, E, NS1) and supporting intracellular virion assembly, without affecting viral entry, RNA replication, or ER membrane remodeling; its pre-mRNA is processed by the minor spliceosome via U12-type introns.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPCS2 is an endoplasmic reticulum-associated host factor co-opted by flaviviruses and hepaciviruses to support viral particle production [#2]. It physically engages viral proteins from distinct virus families, binding the JEV non-structural proteins NS2B and NS5 [#1] and the HCV assembly proteins p7 and E2 along with NS2 [#0]. In JEV infection, SPCS2 is specifically required for the intracellular assembly of infectious virions: its silencing or knockout abolishes infectious particle production while leaving viral attachment, cell entry, RNA replication, protein translation/processing, and ER membrane-invaginated vesicle formation intact [#2]. Mechanistically, SPCS2 maintains the stability of selected viral proteins, since its depletion promotes degradation of the structural proteins prM and E and the non-structural protein NS1, but not NS2B [#3]. At the level of its own expression, the SPCS2 pre-mRNA carries U12-type introns and is processed by the minor spliceosome [#4]. Beyond these findings, no endogenous cellular substrate or non-viral physiological function of SPCS2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that SPCS2 expression depends on minor spliceosome processing, defining a layer of regulation over its own production.\",\n      \"evidence\": \"RNA splicing analysis in cells from individuals carrying RNPC3 mutations, with U11/U12 di-snRNP formation assays\",\n      \"pmids\": [\"24480542\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No follow-up on SPCS2 protein function or how reduced splicing translates to phenotype\",\n        \"Does not address the cellular role of the SPCS2 protein itself\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SPCS2 as a physical interactor of HCV assembly machinery, the first link between this host protein and viral particle formation.\",\n      \"evidence\": \"Affinity purification mass spectrometry in HCV-infected cells with epitope-tagged viral constructs\",\n      \"pmids\": [\"38230952\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Interaction not validated by an orthogonal method in this study\",\n        \"Functional consequence for HCV replication or assembly not tested\",\n        \"Direct vs. indirect binding not resolved\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the SPCS2-virus interaction to a second virus family and pinned down its functional role as an assembly factor, distinguishing it from entry and replication steps.\",\n      \"evidence\": \"Co-IP/MS identification of JEV NS2B and NS5 binding, combined with siRNA/CRISPR knockout and stepwise dissection of the JEV life cycle\",\n      \"pmids\": [\"41910145\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular basis of how SPCS2 promotes virion assembly is unresolved\",\n        \"Whether NS2B/NS5 binding is required for the assembly function is untested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a mechanistic basis for the assembly defect by showing SPCS2 selectively stabilizes specific viral proteins.\",\n      \"evidence\": \"Immunoblotting of viral protein levels in SPCS2 knockout JEV-infected cells\",\n      \"pmids\": [\"41910145\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Degradation pathway acting on prM/E/NS1 in SPCS2 absence not identified\",\n        \"Whether stabilization is direct or via a downstream chaperone/protease activity unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous cellular function of SPCS2 and its normal substrates remain undefined; all functional data derive from viral hijacking contexts.\",\n      \"evidence\": \"No discovery in the corpus addresses a host physiological role independent of viral infection\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No native cellular substrate or partner identified\",\n        \"Mechanism by which SPCS2 stabilizes proteins is uncharacterized\",\n        \"No structural model of SPCS2 or its viral-protein interfaces\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NS2B\", \"NS5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}