{"gene":"MBTPS1","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1998,"finding":"MBTPS1 (Site-1 Protease, S1P) was molecularly identified as a 1052-amino-acid membrane-bound subtilisin-like serine protease that cleaves SREBPs in the ER luminal loop. Cloning was achieved by functional complementation of SRD-12B cells (S1P-deficient CHO cholesterol auxotrophs) using a PLAP-BP2 reporter construct; S1P expression restored Site-1 cleavage and PLAP secretion. S1P is sterol-regulated and is the initiating protease controlling lipid metabolism in animal cells.","method":"Functional complementation cloning in S1P-deficient SRD-12B cells, PLAP secretion reporter assay, cDNA transfection","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — original cloning with in vitro functional reconstitution and rigorous genetic complementation","pmids":["9809072"],"is_preprint":false},{"year":1999,"finding":"MBTPS1 (SKI-1) was independently identified as a widely expressed type I membrane-bound proprotein convertase with subtilisin/kexin-like serine protease activity. It cleaves pro-BDNF at an RGLT↓SL bond generating a 28-kDa product from the 32-kDa precursor. SKI-1 is processed in the ER into 120-kDa and 106-kDa membrane-bound forms differing in N-glycosylation, and a shed 98-kDa form appears late in the secretory pathway. Immunocytochemistry showed localization to the Golgi apparatus and punctate endosome-like structures.","method":"RT-PCR cloning, in vitro cleavage assay of pro-BDNF, metabolic labeling, immunoprecipitation, immunocytochemistry of stably transfected HK293 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods: in vitro cleavage assay, glycosylation analysis, subcellular localization with functional context","pmids":["9990022"],"is_preprint":false},{"year":1999,"finding":"MBTPS1-mediated proteolysis of SREBPs is transport-dependent: SCAP escorts SREBPs from the ER to the Golgi where S1P cleaves them. Relocating active S1P from Golgi to ER (by brefeldin A treatment or by fusing the KDEL ER-retention signal to S1P) bypasses the SCAP requirement and renders SREBP cleavage sterol-insensitive. This demonstrated that S1P normally resides in and acts at the Golgi, and that regulated ER-to-Golgi transport of the SCAP-SREBP complex is the key control point.","method":"Brefeldin A treatment, KDEL-S1P fusion construct, cell-based SREBP cleavage assays, genetic complementation with SCAP-deficient cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with gain-of-function constructs and pharmacological perturbation establishing causal mechanism","pmids":["10619424"],"is_preprint":false},{"year":2000,"finding":"MBTPS1 (S1P) and Site-2 protease (S2P) are required for ER stress-induced cleavage of ATF6, a membrane-bound transcription factor that activates the unfolded protein response. ATF6 processing was completely blocked in S2P-deficient cells and partially blocked in S1P-deficient cells. ATF6 processing required the same RxxL and Asn/Pro sequence motifs needed for SREBP processing by S1P/S2P. Unlike SREBP processing, ATF6 processing did not require SCAP.","method":"Cell-based proteolysis assays in S1P- and S2P-deficient mutant cell lines, site-directed mutagenesis of ATF6 cleavage motifs, GRP78 induction assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — genetic loss-of-function in defined mutant cell lines with multiple substrates and mutagenesis controls","pmids":["11163209"],"is_preprint":false},{"year":2001,"finding":"MBTPS1 (SKI-1) cleaves pro-BDNF at the Arg-Gly-Leu-Thr↓Ser-Leu site in the ER/trans-Golgi network to generate a 28-kDa intermediate. Mutation of Arg54 to Ala abolished this cleavage. The 28-kDa form is not an obligatory intermediate for mature 14-kDa BDNF generation; blocking furin-like enzymes (with α1-PDX) abolishes mature BDNF but does not cause 28-kDa accumulation.","method":"Vaccinia virus expression system, metabolic labeling, immunoprecipitation, in vitro mutagenesis (R54A), furin inhibitor (α1-PDX)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis of cleavage site plus pharmacological inhibition establishing S1P as responsible protease","pmids":["11152678"],"is_preprint":false},{"year":2002,"finding":"ATF6 is transported from the ER to the Golgi in response to ER stress, where it is cleaved in its luminal domain by MBTPS1 (Site-1 protease). The conserved CD1 region of ATF6's luminal domain is required for ER-to-Golgi translocation, while the CD2 region is required for S1P cleavage. The ATF6 luminal domain alone is sufficient to sense ER stress and cause Golgi translocation when fused to another ER transmembrane protein (LZIP).","method":"ATF6 domain deletion and chimeric fusion constructs (ATF6-LZIP), cell-based ER stress assays, subcellular localization studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — domain mapping with chimeric constructs and functional readouts in multiple cell contexts","pmids":["11821395"],"is_preprint":false},{"year":2009,"finding":"A hypomorphic ENU-induced missense mutation in Mbtps1 (encoding S1P) causes enhanced susceptibility to DSS-induced colitis in mice. The mutation diminishes S1P's non-redundant role in the ATF6-dependent unfolded protein response, resulting in reduced levels of ER chaperones GRP78 (BiP) and GRP94 in the colon upon DSS challenge. Bone marrow chimera experiments established that the S1P requirement is in non-hematopoietic cells.","method":"ENU mutagenesis screen, DSS colitis model, bone marrow chimera experiments, Western blot for ER chaperones (GRP78, GRP94)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with bone marrow chimeras and molecular readouts establishing non-hematopoietic cell-autonomous requirement","pmids":["19202076"],"is_preprint":false},{"year":2008,"finding":"MBTPS1 (SKI-1/S1P) belongs to the subtilisin/kexin-like serine protease superfamily and is classified within a distinct subfamily. Its catalytic domain shares the conserved Asp, His, Ser catalytic triad of subtilases. SKI-1 is distinguished by cleavage at non-basic residues (e.g., hydrophobic/small residues at P1), contrasting with the basic-residue specificity of other proprotein convertases.","method":"Comparative sequence analysis, multiple sequence alignment, 3D homology modeling of catalytic domain","journal":"Protein science : a publication of the Protein Society","confidence":"Medium","confidence_rationale":"Tier 4 computational/comparative — but foundational classification, widely validated by experimental work in other papers","pmids":["9070434"],"is_preprint":false},{"year":2008,"finding":"MBTPS1 (SKI-1/S1P) is one of nine mammalian secretory serine proteases of the subtilisin type. Together with PCSK9, it forms a subclass that cleaves at non-basic residues and regulates cholesterol and lipid homeostasis. SKI-1/S1P activates SREBPs and ATF6 among other substrates, and processes viral glycoproteins. It is considered an attractive therapeutic target.","method":"Review integrating biochemical, genetic, and pharmacological data from multiple experimental systems","journal":"Nature reviews. Drug discovery","confidence":"Medium","confidence_rationale":"Tier 3 — synthesis review with strong experimental basis across the field","pmids":["22679642"],"is_preprint":false},{"year":2008,"finding":"MBTPS1 (SKI-1/S1P) is activated in the ER by autocatalytic removal of its prodomain, generating the 120-kDa and 106-kDa membrane-bound active forms, followed by shedding of the 98-kDa ectodomain into the secretory pathway. The convertase is enriched in the Golgi and endosomal compartments and exhibits a broad substrate range including SREBPs, ATF6, CREB/ATF family members, and viral glycoproteins.","method":"Review synthesizing biochemical processing assays, cell-based localization experiments, and substrate identification studies","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — comprehensive review with strong experimental grounding from the convertase field","pmids":["18343183"],"is_preprint":false},{"year":2023,"finding":"The lipogenesis cascade Scap-SREBP1-S1P/S2P orchestrates the spatiotemporal activation of NF-κB. Scap and SREBP1 form a super-complex with IκBα to tether NF-κB near the ER. Upon LPS stimulation, Scap transports the complex to the Golgi where MBTPS1 (S1P) cleaves SREBP1, liberating IκBα for IKK-mediated phosphorylation and NF-κB activation. Loss of Scap or inhibition of S1P/S2P diminishes LPS-induced NF-κB activation; SREBP1 deficiency augments it.","method":"Genetic knockouts and siRNA knockdown of Scap, SREBP1; pharmacological S1P/S2P inhibition; co-immunoprecipitation of Scap-SREBP1-IκBα super-complex; LPS stimulation assays; NF-κB reporter assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal genetic and pharmacological approaches with biochemical complex identification and functional NF-κB readout","pmids":["37267109"],"is_preprint":false}],"current_model":"MBTPS1 encodes Site-1 Protease (S1P/SKI-1), a membrane-bound subtilisin-like serine protease that resides primarily in the Golgi and cleaves multiple substrates at non-basic residues, including SREBPs (to regulate lipid/cholesterol homeostasis via SCAP-dependent ER-to-Golgi transport), ATF6 (to activate the unfolded protein response to ER stress independently of SCAP), pro-BDNF, and viral glycoproteins; it also participates in NF-κB activation by cleaving SREBP1 within a Scap-SREBP1-IκBα complex at the Golgi, and its loss-of-function impairs the ATF6-driven UPR in intestinal epithelial cells, causing enhanced susceptibility to colitis."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of S1P as the initiating protease for SREBP cleavage resolved a long-sought enzymatic activity controlling cholesterol and lipid gene regulation, establishing MBTPS1 as the gatekeeper of sterol-responsive proteolysis.","evidence":"Functional complementation cloning using S1P-deficient SRD-12B CHO cells and a PLAP-BP2 secretion reporter","pmids":["9809072"],"confidence":"High","gaps":["Subcellular site of cleavage not yet mapped","Substrate specificity beyond SREBPs unknown","Mechanism of sterol regulation of S1P activity not resolved"]},{"year":1999,"claim":"Independent identification of S1P as SKI-1, a proprotein convertase cleaving pro-BDNF at a non-basic site, expanded the enzyme's substrate repertoire beyond SREBPs and revealed that it is processed autocatalytically into multiple glycoforms localized to the Golgi and endosomal compartments.","evidence":"In vitro cleavage assays of pro-BDNF, metabolic labeling and immunoprecipitation, and immunocytochemistry of stably transfected HK293 cells","pmids":["9990022"],"confidence":"High","gaps":["Cleavage-site determinants for non-basic substrates not defined","Functional significance of shed 98-kDa ectodomain unknown"]},{"year":1999,"claim":"Demonstrating that SCAP-dependent ER-to-Golgi transport is the sterol-regulated step—not S1P activity itself—resolved how cells restrict SREBP processing to sterol-depleted conditions; relocating S1P to the ER bypassed SCAP and made cleavage constitutive.","evidence":"Brefeldin A treatment and KDEL-S1P ER-retention fusion constructs in SCAP-deficient cells","pmids":["10619424"],"confidence":"High","gaps":["Mechanism of SCAP sterol sensing not addressed","Whether other substrates also require regulated transport to the Golgi unknown"]},{"year":2000,"claim":"Showing that S1P and S2P are both required for ATF6 cleavage during ER stress—but independently of SCAP—established S1P as a shared effector protease linking lipid homeostasis and the UPR through distinct upstream regulatory mechanisms.","evidence":"Cell-based proteolysis assays in S1P- and S2P-deficient mutant CHO lines, site-directed mutagenesis of ATF6 cleavage motifs","pmids":["11163209"],"confidence":"High","gaps":["Mechanism by which ATF6 reaches the Golgi without SCAP not identified","Whether S1P directly senses ER stress or only acts constitutively in the Golgi unclear"]},{"year":2001,"claim":"Precise mapping of the pro-BDNF cleavage site (R54) and demonstration that S1P cleavage produces a 28-kDa intermediate—not an obligatory precursor for mature BDNF—clarified the processing hierarchy of pro-BDNF through sequential convertases.","evidence":"R54A site-directed mutagenesis and furin inhibitor α1-PDX in a vaccinia virus expression system with metabolic labeling","pmids":["11152678"],"confidence":"High","gaps":["Physiological role of the 28-kDa intermediate in vivo not established","Whether S1P processes other neurotrophins unknown"]},{"year":2002,"claim":"Domain mapping of ATF6 identified separate luminal determinants for ER-stress sensing/Golgi translocation (CD1) and S1P cleavage (CD2), establishing that stress sensing and proteolytic processing are mechanistically separable events.","evidence":"ATF6 deletion constructs and chimeric ATF6-LZIP fusions with ER stress assays and localization studies","pmids":["11821395"],"confidence":"High","gaps":["Identity of the ER-stress sensor interacting with CD1 not determined","Structural basis of S1P recognition of the CD2 domain unknown"]},{"year":2009,"claim":"An in vivo hypomorphic Mbtps1 mutation revealed that S1P is non-redundantly required for the ATF6-dependent UPR in intestinal epithelial cells, providing the first genetic evidence that diminished S1P activity predisposes to colitis through defective ER chaperone induction.","evidence":"ENU-induced missense Mbtps1 mutation in mice, DSS colitis model, bone marrow chimera experiments, Western blot for GRP78/GRP94","pmids":["19202076"],"confidence":"High","gaps":["Precise residue affected by ENU mutation and its structural consequence not detailed here","Whether SREBP-dependent lipid pathways also contribute to the colitis phenotype not resolved","Human disease relevance of MBTPS1 loss-of-function in IBD not established"]},{"year":2023,"claim":"Discovery that Scap–SREBP1–IκBα form a super-complex tethering NF-κB near the ER, and that S1P-mediated cleavage of SREBP1 at the Golgi liberates IκBα for IKK phosphorylation, uncovered a previously unknown role for the lipogenesis cascade in spatiotemporal NF-κB activation upon LPS stimulation.","evidence":"Co-immunoprecipitation of Scap-SREBP1-IκBα complex, Scap and SREBP1 genetic knockouts, S1P/S2P pharmacological inhibition, LPS stimulation, NF-κB reporter assays","pmids":["37267109"],"confidence":"High","gaps":["Whether this NF-κB mechanism operates in non-macrophage cell types not shown","Direct structural evidence for the ternary Scap-SREBP1-IκBα complex lacking","Whether S1P cleavage of SREBP1 in this context differs kinetically from sterol-regulated processing unknown"]},{"year":null,"claim":"Key open questions include the structural basis for S1P's unusual non-basic substrate specificity, whether S1P has additional physiological substrates beyond SREBPs/ATF6/BDNF/viral glycoproteins, and the in vivo significance of the shed 98-kDa ectodomain form in the secretory pathway.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal structure of S1P catalytic domain with substrate resolved","Full in vivo substrate repertoire not systematically defined","Functional role of shed S1P ectodomain unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,4,10]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2,5,10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4,9]}],"complexes":[],"partners":["SREBF1","SREBF2","ATF6","SCAP","MBTPS2","BDNF"],"other_free_text":[]},"mechanistic_narrative":"MBTPS1 (Site-1 Protease/SKI-1) is a Golgi-resident, membrane-bound subtilisin-like serine protease that initiates the regulated intramembrane proteolysis of multiple type II membrane-bound transcription factors, linking cholesterol/lipid homeostasis, the unfolded protein response, and innate immune signaling. S1P cleaves SREBPs in the Golgi following SCAP-dependent ER-to-Golgi transport, a sterol-regulated step that constitutes the key control point for lipid metabolism; it similarly cleaves ATF6 during ER stress in a SCAP-independent manner to activate UPR target genes [PMID:9809072, PMID:10619424, PMID:11163209]. S1P also processes pro-BDNF at a non-basic RGLT↓SL motif and viral glycoproteins, distinguishing it from other proprotein convertases that require basic-residue cleavage sites [PMID:9990022, PMID:11152678]. Beyond lipid regulation, S1P participates in NF-κB activation by cleaving SREBP1 within a Golgi-localized Scap–SREBP1–IκBα super-complex upon LPS stimulation, and its hypomorphic loss in mice impairs the ATF6-driven UPR in intestinal epithelial cells, causing enhanced susceptibility to colitis [PMID:37267109, PMID:19202076]."},"prefetch_data":{"uniprot":{"accession":"Q14703","full_name":"Membrane-bound transcription factor site-1 protease","aliases":["Endopeptidase S1P","Subtilisin/kexin-isozyme 1","SKI-1"],"length_aa":1052,"mass_kda":117.7,"function":"Serine protease that cleaves after hydrophobic or small residues, provided that Arg or Lys is in position P4: known substrates include SREBF1/SREBP1, SREBF2/SREBP2, BDNF, GNPTAB, ATF6, ATF6B and FAM20C (PubMed:10644685, PubMed:12782636, PubMed:21719679, PubMed:34349020). Cleaves substrates after Arg-Ser-Val-Leu (SREBP2), Arg-His-Leu-Leu (ATF6), Arg-Gly-Leu-Thr (BDNF) and its own propeptide after Arg-Arg-Leu-Leu (PubMed:10644685, PubMed:21719679). Catalyzes the first step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:12782636). Also mediates the first step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:12782636). Mediates the protein cleavage of GNPTAB into subunit alpha and beta, thereby participating in biogenesis of lysosomes (PubMed:21719679). Cleaves the propeptide from FAM20C which is required for FAM20C secretion from the Golgi apparatus membrane and for enhancement of FAM20C kinase activity, promoting osteoblast differentiation and biomineralization (PubMed:34349020). Involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes (PubMed:21719679, PubMed:30046013). It is required for the activation of CREB3L2/BBF2H7, a transcriptional activator of MIA3/TANGO and other genes controlling mega vesicle formation (PubMed:30046013). Therefore, it plays a key role in the regulation of mega vesicle-mediated collagen trafficking (PubMed:30046013). Promotes FAD binding to the ETFA/ETFB complex and is therefore involved in mitochondrial respiratory chain regulation (PubMed:35362222). In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the first step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression (PubMed:16417584)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Secreted; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q14703/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MBTPS1","classification":"Not Classified","n_dependent_lines":747,"n_total_lines":1208,"dependency_fraction":0.6183774834437086},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MBTPS1","total_profiled":1310},"omim":[{"mim_id":"621252","title":"CATARACT, ALOPECIA, ORAL MUCOSAL DISORDER, AND PSORIASIS-LIKE SYNDROME; CAOP","url":"https://www.omim.org/entry/621252"},{"mim_id":"618392","title":"SPONDYLOEPIPHYSEAL DYSPLASIA, KONDO-FU TYPE; SEDKF","url":"https://www.omim.org/entry/618392"},{"mim_id":"611998","title":"cAMP RESPONSE ELEMENT-BINDING PROTEIN 3-LIKE 3; CREB3L3","url":"https://www.omim.org/entry/611998"},{"mim_id":"604026","title":"GOLGI SNAP RECEPTOR COMPLEX MEMBER 1; GOSR1","url":"https://www.omim.org/entry/604026"},{"mim_id":"603355","title":"MEMBRANE-BOUND TRANSCRIPTION FACTOR PROTEASE, SITE 1; MBTPS1","url":"https://www.omim.org/entry/603355"}],"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/MBTPS1"},"hgnc":{"alias_symbol":["S1P","KIAA0091","SKI-1","PCSK8"],"prev_symbol":[]},"alphafold":{"accession":"Q14703","domains":[{"cath_id":"3.30.70,3.30.70","chopping":"42-139","consensus_level":"medium","plddt":82.362,"start":42,"end":139},{"cath_id":"3.40.50.200","chopping":"194-479","consensus_level":"high","plddt":91.505,"start":194,"end":479},{"cath_id":"3.40.50.880","chopping":"620-911","consensus_level":"high","plddt":89.002,"start":620,"end":911}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14703","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14703-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14703-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MBTPS1","jax_strain_url":"https://www.jax.org/strain/search?query=MBTPS1"},"sequence":{"accession":"Q14703","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14703.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14703/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14703"}},"corpus_meta":[{"pmid":"16151014","id":"PMC_16151014","title":"Lymphocyte 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cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9809072","id":"PMC_9809072","title":"Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9809072","citation_count":333,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12177166","id":"PMC_12177166","title":"Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes.","date":"2002","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/12177166","citation_count":302,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22934019","id":"PMC_22934019","title":"The endoplasmic reticulum stress response in aging and age-related 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intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18343183","id":"PMC_18343183","title":"The activation and physiological functions of the proprotein convertases.","date":"2008","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18343183","citation_count":253,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17124500","id":"PMC_17124500","title":"Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17124500","citation_count":249,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9990022","id":"PMC_9990022","title":"Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9990022","citation_count":241,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14645851","id":"PMC_14645851","title":"The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14645851","citation_count":182,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45578,"output_tokens":985,"usd":0.075755},"stage2":{"model":"claude-opus-4-6","input_tokens":4019,"output_tokens":1159,"usd":0.073605},"total_usd":0.419095,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58493,"output_tokens":4037,"usd":0.118017},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6979,"output_tokens":2650,"usd":0.151718}},"stage1_raw":"Looking through these 100 papers, I need to identify those actually about MBTPS1 (membrane-bound transcription factor peptidase, site 1 — also known as S1P protease/Site-1 Protease). The vast majority of these papers are about sphingosine-1-phosphate (S1P) signaling and its receptors, which is a completely different \"S1P\" — a symbol collision. MBTPS1 encodes Site-1 Protease (S1P), a serine protease involved in SREBP activation and the unfolded protein response.\n\nOnly paper [11] (PMID 19202076) and paper [59] (PMID 37267109) appear to be directly about MBTPS1/Site-1 Protease function.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"A hypomorphic ENU-induced missense mutation in Mbtps1 (encoding Site-1 Protease, S1P) causes enhanced susceptibility to DSS-induced colitis by impairing the ATF6-dependent unfolded protein response (UPR); S1P cleaves and activates ATF6, and its loss reduces levels of ER chaperones GRP78 (BiP) and GRP94 in the colon. Bone marrow chimera experiments established that S1P function is required in non-hematopoietic cells for a normal UPR and protection from colitis.\",\n      \"method\": \"ENU mutagenesis, in vivo DSS colitis model, bone marrow chimeric mice, Western blot for GRP78/GRP94\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined molecular phenotype (reduced UPR chaperones) and cell-type specificity established by bone marrow chimeras\",\n      \"pmids\": [\"19202076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The Scap-SREBP1-S1P/S2P lipogenesis cascade orchestrates spatiotemporal NF-κB activation: upon LPS stimulation, Scap transports a super-complex (containing SREBP1, IκBα, and NF-κB) from the ER to the Golgi, where Site-1 Protease (S1P/MBTPS1) cleaves SREBP1, liberating IκBα for IKK-mediated phosphorylation and downstream NF-κB activation. Inhibition of S1P diminishes LPS-induced NF-κB activation and inflammatory responses.\",\n      \"method\": \"Co-immunoprecipitation of Scap-SREBP1-IκBα super-complex, pharmacological inhibition of S1P, genetic loss-of-function (Scap/SREBP1 knockdown/knockout), subcellular fractionation, reporter assays for NF-κB\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and genetic KO with defined signaling phenotype, but single lab report\",\n      \"pmids\": [\"37267109\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBTPS1 (Site-1 Protease) is a Golgi-localized serine protease that cleaves and activates membrane-tethered transcription factors including SREBPs and ATF6; its protease activity is required for the ATF6-dependent unfolded protein response in non-hematopoietic cells, and it participates in LPS-induced NF-κB activation by cleaving SREBP1 within a Scap-SREBP1-IκBα complex at the Golgi, thereby releasing IκBα for IKK-mediated phosphorylation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification:**\n\nThe retrieved papers [1]-[100] are almost entirely about S1P (sphingosine-1-phosphate) receptors/signaling — these are about the lipid mediator S1P and its receptors (S1PR1-5), NOT about MBTPS1 (Site-1 Protease/SKI-1). This is an alias collision: \"S1P\" is a common abbreviation for both \"sphingosine-1-phosphate\" AND \"Site-1 Protease\" (encoded by MBTPS1). The vast majority of retrieved papers describe sphingosine-1-phosphate biology → EXCLUDE (alias collision).\n\n**KEEP from retrieved papers:**\n- [11] PMID:19202076 — explicitly about Mbtps1 gene, S1P (Site-1 Protease), ATF6, UPR, colitis → KEEP\n\n**KEEP from gene2pubmed-curated papers:**\n- [2] PMID:11163209 — ATF6 processed by Site-1 protease (S1P) and Site-2 protease → KEEP\n- [10] PMID:9070434 — Subtilases superfamily including SKI-1/S1P → KEEP (foundational)\n- [12] PMID:22679642 — Proprotein convertases including SKI-1/S1P → KEEP\n- [13] PMID:11152678 — SKI-1 cleavage of pro-BDNF → KEEP\n- [17] PMID:11821395 — ATF6 luminal domain, site-1 protease cleavage in Golgi → KEEP\n- [19] PMID:9809072 — Molecular identification of S1P (Site-1 Protease), clones MBTPS1 → KEEP\n- [20] PMID:12177166 — SREBP processing, context for S1P substrates → partial; mentions S1P function indirectly → KEEP (foundational SREBP context)\n- [23] PMID:10619424 — Transport-dependent proteolysis of SREBP by S1P, brefeldin A/KDEL experiments → KEEP\n- [25] PMID:18343183 — SKI-1/S1P physiological functions → KEEP\n- [27] PMID:9990022 — SKI-1 identification, cleavage specificity, cellular localization → KEEP\n- [29] PMID:14645851 — SREBP-2 nuclear import (downstream of S1P cleavage) → contextual, EXCLUDE (no direct MBTPS1 mechanism)\n- [59] PMID:37267109 — Scap-SREBP1-S1P/S2P cascade and NF-κB → KEEP\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MBTPS1 (Site-1 Protease, S1P) was molecularly identified as a 1052-amino-acid membrane-bound subtilisin-like serine protease that cleaves SREBPs in the ER luminal loop. Cloning was achieved by functional complementation of SRD-12B cells (S1P-deficient CHO cholesterol auxotrophs) using a PLAP-BP2 reporter construct; S1P expression restored Site-1 cleavage and PLAP secretion. S1P is sterol-regulated and is the initiating protease controlling lipid metabolism in animal cells.\",\n      \"method\": \"Functional complementation cloning in S1P-deficient SRD-12B cells, PLAP secretion reporter assay, cDNA transfection\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning with in vitro functional reconstitution and rigorous genetic complementation\",\n      \"pmids\": [\"9809072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MBTPS1 (SKI-1) was independently identified as a widely expressed type I membrane-bound proprotein convertase with subtilisin/kexin-like serine protease activity. It cleaves pro-BDNF at an RGLT↓SL bond generating a 28-kDa product from the 32-kDa precursor. SKI-1 is processed in the ER into 120-kDa and 106-kDa membrane-bound forms differing in N-glycosylation, and a shed 98-kDa form appears late in the secretory pathway. Immunocytochemistry showed localization to the Golgi apparatus and punctate endosome-like structures.\",\n      \"method\": \"RT-PCR cloning, in vitro cleavage assay of pro-BDNF, metabolic labeling, immunoprecipitation, immunocytochemistry of stably transfected HK293 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods: in vitro cleavage assay, glycosylation analysis, subcellular localization with functional context\",\n      \"pmids\": [\"9990022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MBTPS1-mediated proteolysis of SREBPs is transport-dependent: SCAP escorts SREBPs from the ER to the Golgi where S1P cleaves them. Relocating active S1P from Golgi to ER (by brefeldin A treatment or by fusing the KDEL ER-retention signal to S1P) bypasses the SCAP requirement and renders SREBP cleavage sterol-insensitive. This demonstrated that S1P normally resides in and acts at the Golgi, and that regulated ER-to-Golgi transport of the SCAP-SREBP complex is the key control point.\",\n      \"method\": \"Brefeldin A treatment, KDEL-S1P fusion construct, cell-based SREBP cleavage assays, genetic complementation with SCAP-deficient cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with gain-of-function constructs and pharmacological perturbation establishing causal mechanism\",\n      \"pmids\": [\"10619424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MBTPS1 (S1P) and Site-2 protease (S2P) are required for ER stress-induced cleavage of ATF6, a membrane-bound transcription factor that activates the unfolded protein response. ATF6 processing was completely blocked in S2P-deficient cells and partially blocked in S1P-deficient cells. ATF6 processing required the same RxxL and Asn/Pro sequence motifs needed for SREBP processing by S1P/S2P. Unlike SREBP processing, ATF6 processing did not require SCAP.\",\n      \"method\": \"Cell-based proteolysis assays in S1P- and S2P-deficient mutant cell lines, site-directed mutagenesis of ATF6 cleavage motifs, GRP78 induction assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic loss-of-function in defined mutant cell lines with multiple substrates and mutagenesis controls\",\n      \"pmids\": [\"11163209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MBTPS1 (SKI-1) cleaves pro-BDNF at the Arg-Gly-Leu-Thr↓Ser-Leu site in the ER/trans-Golgi network to generate a 28-kDa intermediate. Mutation of Arg54 to Ala abolished this cleavage. The 28-kDa form is not an obligatory intermediate for mature 14-kDa BDNF generation; blocking furin-like enzymes (with α1-PDX) abolishes mature BDNF but does not cause 28-kDa accumulation.\",\n      \"method\": \"Vaccinia virus expression system, metabolic labeling, immunoprecipitation, in vitro mutagenesis (R54A), furin inhibitor (α1-PDX)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis of cleavage site plus pharmacological inhibition establishing S1P as responsible protease\",\n      \"pmids\": [\"11152678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ATF6 is transported from the ER to the Golgi in response to ER stress, where it is cleaved in its luminal domain by MBTPS1 (Site-1 protease). The conserved CD1 region of ATF6's luminal domain is required for ER-to-Golgi translocation, while the CD2 region is required for S1P cleavage. The ATF6 luminal domain alone is sufficient to sense ER stress and cause Golgi translocation when fused to another ER transmembrane protein (LZIP).\",\n      \"method\": \"ATF6 domain deletion and chimeric fusion constructs (ATF6-LZIP), cell-based ER stress assays, subcellular localization studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain mapping with chimeric constructs and functional readouts in multiple cell contexts\",\n      \"pmids\": [\"11821395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A hypomorphic ENU-induced missense mutation in Mbtps1 (encoding S1P) causes enhanced susceptibility to DSS-induced colitis in mice. The mutation diminishes S1P's non-redundant role in the ATF6-dependent unfolded protein response, resulting in reduced levels of ER chaperones GRP78 (BiP) and GRP94 in the colon upon DSS challenge. Bone marrow chimera experiments established that the S1P requirement is in non-hematopoietic cells.\",\n      \"method\": \"ENU mutagenesis screen, DSS colitis model, bone marrow chimera experiments, Western blot for ER chaperones (GRP78, GRP94)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with bone marrow chimeras and molecular readouts establishing non-hematopoietic cell-autonomous requirement\",\n      \"pmids\": [\"19202076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MBTPS1 (SKI-1/S1P) belongs to the subtilisin/kexin-like serine protease superfamily and is classified within a distinct subfamily. Its catalytic domain shares the conserved Asp, His, Ser catalytic triad of subtilases. SKI-1 is distinguished by cleavage at non-basic residues (e.g., hydrophobic/small residues at P1), contrasting with the basic-residue specificity of other proprotein convertases.\",\n      \"method\": \"Comparative sequence analysis, multiple sequence alignment, 3D homology modeling of catalytic domain\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 4 computational/comparative — but foundational classification, widely validated by experimental work in other papers\",\n      \"pmids\": [\"9070434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MBTPS1 (SKI-1/S1P) is one of nine mammalian secretory serine proteases of the subtilisin type. Together with PCSK9, it forms a subclass that cleaves at non-basic residues and regulates cholesterol and lipid homeostasis. SKI-1/S1P activates SREBPs and ATF6 among other substrates, and processes viral glycoproteins. It is considered an attractive therapeutic target.\",\n      \"method\": \"Review integrating biochemical, genetic, and pharmacological data from multiple experimental systems\",\n      \"journal\": \"Nature reviews. Drug discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — synthesis review with strong experimental basis across the field\",\n      \"pmids\": [\"22679642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MBTPS1 (SKI-1/S1P) is activated in the ER by autocatalytic removal of its prodomain, generating the 120-kDa and 106-kDa membrane-bound active forms, followed by shedding of the 98-kDa ectodomain into the secretory pathway. The convertase is enriched in the Golgi and endosomal compartments and exhibits a broad substrate range including SREBPs, ATF6, CREB/ATF family members, and viral glycoproteins.\",\n      \"method\": \"Review synthesizing biochemical processing assays, cell-based localization experiments, and substrate identification studies\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — comprehensive review with strong experimental grounding from the convertase field\",\n      \"pmids\": [\"18343183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lipogenesis cascade Scap-SREBP1-S1P/S2P orchestrates the spatiotemporal activation of NF-κB. Scap and SREBP1 form a super-complex with IκBα to tether NF-κB near the ER. Upon LPS stimulation, Scap transports the complex to the Golgi where MBTPS1 (S1P) cleaves SREBP1, liberating IκBα for IKK-mediated phosphorylation and NF-κB activation. Loss of Scap or inhibition of S1P/S2P diminishes LPS-induced NF-κB activation; SREBP1 deficiency augments it.\",\n      \"method\": \"Genetic knockouts and siRNA knockdown of Scap, SREBP1; pharmacological S1P/S2P inhibition; co-immunoprecipitation of Scap-SREBP1-IκBα super-complex; LPS stimulation assays; NF-κB reporter assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal genetic and pharmacological approaches with biochemical complex identification and functional NF-κB readout\",\n      \"pmids\": [\"37267109\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBTPS1 encodes Site-1 Protease (S1P/SKI-1), a membrane-bound subtilisin-like serine protease that resides primarily in the Golgi and cleaves multiple substrates at non-basic residues, including SREBPs (to regulate lipid/cholesterol homeostasis via SCAP-dependent ER-to-Golgi transport), ATF6 (to activate the unfolded protein response to ER stress independently of SCAP), pro-BDNF, and viral glycoproteins; it also participates in NF-κB activation by cleaving SREBP1 within a Scap-SREBP1-IκBα complex at the Golgi, and its loss-of-function impairs the ATF6-driven UPR in intestinal epithelial cells, causing enhanced susceptibility to colitis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MBTPS1 (Site-1 Protease, S1P) is a Golgi-localized serine protease that activates membrane-bound transcription factors through regulated intramembrane proteolysis. S1P cleaves ATF6 to initiate the unfolded protein response, and its activity in non-hematopoietic cells is required for maintaining ER chaperone levels (GRP78, GRP94) and protecting against intestinal inflammation [PMID:19202076]. S1P also cleaves SREBP1 within a Scap–SREBP1–IκBα super-complex at the Golgi following LPS stimulation, liberating IκBα for IKK-mediated phosphorylation and thereby enabling NF-κB activation and inflammatory signaling [PMID:37267109].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that S1P is required in vivo for ATF6-dependent UPR resolved how ER stress sensing is transduced through Golgi proteolysis in epithelial tissues, and revealed that loss of this activity sensitizes the colon to inflammatory injury.\",\n      \"evidence\": \"Hypomorphic ENU-induced Mbtps1 mutation in mice with DSS colitis model, bone marrow chimeras, and Western blot for GRP78/GRP94\",\n      \"pmids\": [\"19202076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether S1P-mediated ATF6 cleavage is rate-limiting for UPR in other epithelial tissues was not tested\",\n        \"The structural basis for the hypomorphic mutation's effect on catalytic activity was not determined\",\n        \"Whether SREBP cleavage by S1P contributes independently to the colitis phenotype was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that S1P cleaves SREBP1 within a Scap–SREBP1–IκBα super-complex at the Golgi linked the lipogenesis proteolytic cascade to innate immune NF-κB activation, revealing a non-canonical role for S1P beyond transcription factor processing.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, pharmacological S1P inhibition, Scap/SREBP1 knockout, subcellular fractionation, and NF-κB reporter assays in LPS-stimulated cells\",\n      \"pmids\": [\"37267109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-laboratory report; independent replication of the Scap–SREBP1–IκBα super-complex has not been reported\",\n        \"The precise S1P cleavage site on SREBP1 relevant to IκBα release was not mapped\",\n        \"Whether this mechanism operates in non-macrophage cell types is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Unresolved: the full spectrum of S1P substrates beyond SREBPs and ATF6, the structural determinants of substrate selectivity, and whether S1P's roles in UPR and NF-κB signaling are coordinated or independent remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unbiased substrate profiling of S1P has been reported in the timeline\",\n        \"No structural model of S1P–substrate recognition is available\",\n        \"Cross-talk between ATF6-UPR and NF-κB arms of S1P signaling has not been addressed\"\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:0005794\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008150\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SREBF1\",\n      \"ATF6\",\n      \"SCAP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MBTPS1 (Site-1 Protease/SKI-1) is a Golgi-resident, membrane-bound subtilisin-like serine protease that initiates the regulated intramembrane proteolysis of multiple type II membrane-bound transcription factors, linking cholesterol/lipid homeostasis, the unfolded protein response, and innate immune signaling. S1P cleaves SREBPs in the Golgi following SCAP-dependent ER-to-Golgi transport, a sterol-regulated step that constitutes the key control point for lipid metabolism; it similarly cleaves ATF6 during ER stress in a SCAP-independent manner to activate UPR target genes [PMID:9809072, PMID:10619424, PMID:11163209]. S1P also processes pro-BDNF at a non-basic RGLT↓SL motif and viral glycoproteins, distinguishing it from other proprotein convertases that require basic-residue cleavage sites [PMID:9990022, PMID:11152678]. Beyond lipid regulation, S1P participates in NF-κB activation by cleaving SREBP1 within a Golgi-localized Scap–SREBP1–IκBα super-complex upon LPS stimulation, and its hypomorphic loss in mice impairs the ATF6-driven UPR in intestinal epithelial cells, causing enhanced susceptibility to colitis [PMID:37267109, PMID:19202076].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of S1P as the initiating protease for SREBP cleavage resolved a long-sought enzymatic activity controlling cholesterol and lipid gene regulation, establishing MBTPS1 as the gatekeeper of sterol-responsive proteolysis.\",\n      \"evidence\": \"Functional complementation cloning using S1P-deficient SRD-12B CHO cells and a PLAP-BP2 secretion reporter\",\n      \"pmids\": [\"9809072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Subcellular site of cleavage not yet mapped\",\n        \"Substrate specificity beyond SREBPs unknown\",\n        \"Mechanism of sterol regulation of S1P activity not resolved\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Independent identification of S1P as SKI-1, a proprotein convertase cleaving pro-BDNF at a non-basic site, expanded the enzyme's substrate repertoire beyond SREBPs and revealed that it is processed autocatalytically into multiple glycoforms localized to the Golgi and endosomal compartments.\",\n      \"evidence\": \"In vitro cleavage assays of pro-BDNF, metabolic labeling and immunoprecipitation, and immunocytochemistry of stably transfected HK293 cells\",\n      \"pmids\": [\"9990022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cleavage-site determinants for non-basic substrates not defined\",\n        \"Functional significance of shed 98-kDa ectodomain unknown\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that SCAP-dependent ER-to-Golgi transport is the sterol-regulated step—not S1P activity itself—resolved how cells restrict SREBP processing to sterol-depleted conditions; relocating S1P to the ER bypassed SCAP and made cleavage constitutive.\",\n      \"evidence\": \"Brefeldin A treatment and KDEL-S1P ER-retention fusion constructs in SCAP-deficient cells\",\n      \"pmids\": [\"10619424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of SCAP sterol sensing not addressed\",\n        \"Whether other substrates also require regulated transport to the Golgi unknown\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showing that S1P and S2P are both required for ATF6 cleavage during ER stress—but independently of SCAP—established S1P as a shared effector protease linking lipid homeostasis and the UPR through distinct upstream regulatory mechanisms.\",\n      \"evidence\": \"Cell-based proteolysis assays in S1P- and S2P-deficient mutant CHO lines, site-directed mutagenesis of ATF6 cleavage motifs\",\n      \"pmids\": [\"11163209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which ATF6 reaches the Golgi without SCAP not identified\",\n        \"Whether S1P directly senses ER stress or only acts constitutively in the Golgi unclear\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Precise mapping of the pro-BDNF cleavage site (R54) and demonstration that S1P cleavage produces a 28-kDa intermediate—not an obligatory precursor for mature BDNF—clarified the processing hierarchy of pro-BDNF through sequential convertases.\",\n      \"evidence\": \"R54A site-directed mutagenesis and furin inhibitor α1-PDX in a vaccinia virus expression system with metabolic labeling\",\n      \"pmids\": [\"11152678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological role of the 28-kDa intermediate in vivo not established\",\n        \"Whether S1P processes other neurotrophins unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Domain mapping of ATF6 identified separate luminal determinants for ER-stress sensing/Golgi translocation (CD1) and S1P cleavage (CD2), establishing that stress sensing and proteolytic processing are mechanistically separable events.\",\n      \"evidence\": \"ATF6 deletion constructs and chimeric ATF6-LZIP fusions with ER stress assays and localization studies\",\n      \"pmids\": [\"11821395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the ER-stress sensor interacting with CD1 not determined\",\n        \"Structural basis of S1P recognition of the CD2 domain unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"An in vivo hypomorphic Mbtps1 mutation revealed that S1P is non-redundantly required for the ATF6-dependent UPR in intestinal epithelial cells, providing the first genetic evidence that diminished S1P activity predisposes to colitis through defective ER chaperone induction.\",\n      \"evidence\": \"ENU-induced missense Mbtps1 mutation in mice, DSS colitis model, bone marrow chimera experiments, Western blot for GRP78/GRP94\",\n      \"pmids\": [\"19202076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise residue affected by ENU mutation and its structural consequence not detailed here\",\n        \"Whether SREBP-dependent lipid pathways also contribute to the colitis phenotype not resolved\",\n        \"Human disease relevance of MBTPS1 loss-of-function in IBD not established\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that Scap–SREBP1–IκBα form a super-complex tethering NF-κB near the ER, and that S1P-mediated cleavage of SREBP1 at the Golgi liberates IκBα for IKK phosphorylation, uncovered a previously unknown role for the lipogenesis cascade in spatiotemporal NF-κB activation upon LPS stimulation.\",\n      \"evidence\": \"Co-immunoprecipitation of Scap-SREBP1-IκBα complex, Scap and SREBP1 genetic knockouts, S1P/S2P pharmacological inhibition, LPS stimulation, NF-κB reporter assays\",\n      \"pmids\": [\"37267109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this NF-κB mechanism operates in non-macrophage cell types not shown\",\n        \"Direct structural evidence for the ternary Scap-SREBP1-IκBα complex lacking\",\n        \"Whether S1P cleavage of SREBP1 in this context differs kinetically from sterol-regulated processing unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis for S1P's unusual non-basic substrate specificity, whether S1P has additional physiological substrates beyond SREBPs/ATF6/BDNF/viral glycoproteins, and the in vivo significance of the shed 98-kDa ectodomain form in the secretory pathway.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No crystal structure of S1P catalytic domain with substrate resolved\",\n        \"Full in vivo substrate repertoire not systematically defined\",\n        \"Functional role of shed S1P ectodomain unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2, 5, 10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SREBF1\",\n      \"SREBF2\",\n      \"ATF6\",\n      \"SCAP\",\n      \"MBTPS2\",\n      \"BDNF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}