{"gene":"MBTPS1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"Human SKI-1/S1P (MBTPS1) is a Ca2+-dependent subtilisin-like proteinase with optimal cleavage activity at pH 6.5. Its prosegment is processed into 26-, 24-, 14-, 10-, and 8-kDa fragments within the ER, some remaining tightly associated with the enzyme. In vitro, recombinant prosegments inhibit SKI-1 activity with Ki ~100–200 nM. The enzyme cleaves substrates including SREBP-2 and pro-BDNF mimicking peptides; mutagenesis of the RRLL(186)-containing prosegment peptide defined key P and P' residues for cleavage.","method":"Biochemical characterization in LoVo cells; N-terminal sequencing and mass spectrometry; in vitro enzymatic assay with secreted recombinant SKI-1; synthetic peptide processing; site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified enzyme, mutagenesis of substrate residues, mass spectrometry mapping of cleavage sites, multiple orthogonal methods in single rigorous study","pmids":["10644685"],"is_preprint":false},{"year":2007,"finding":"SKI-1/S1P (MBTPS1) undergoes three sequential autocatalytic prosegment processing steps and an ectodomain shedding producing a membrane-bound stump (St-1, aa 954–1052) at KHQKLL(953). A smaller C-terminal fragment St-2 is generated by an internal alternate translation event at Met(990), confirmed by in vitro transcription/translation; M990A/I/L mutations abolished St-2 generation. Confocal microscopy showed that membrane-bound SKI-1, St-1, and St-2 localize predominantly to the Golgi and can traffic to endosomal/lysosomal compartments but not to the cell surface; the transmembrane domain determines this trafficking. St-1 and St-2 affect ATF6 processing by SKI-1.","method":"Site-directed mutagenesis; in vitro transcription/translation assay; N-terminal sequencing; mass spectrometry; confocal microscopy; deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis validated by in vitro transcription/translation, subcellular localization by confocal microscopy with functional consequence (ATF6 processing), multiple orthogonal methods in one rigorous study","pmids":["17623657"],"is_preprint":false},{"year":2009,"finding":"An ENU-induced hypomorphic missense mutation in Mbtps1 causes enhanced susceptibility to DSS-induced colitis. S1P (MBTPS1) has a non-redundant function in the ATF6-dependent unfolded protein response (UPR); woodrat mice with diminished S1P activity show reduced levels of ER chaperones GRP78 (BiP) and GRP94 in the colon upon DSS treatment. Bone marrow chimera experiments established that S1P function is required in non-hematopoietic cells for a normal UPR and protection from colitis.","method":"ENU mutagenesis; DSS colitis model; Western blot for GRP78/GRP94; bone marrow chimeric mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via hypomorphic allele, bone marrow chimera dissection of cell-type requirement, specific molecular readout (chaperone levels), replicated in vivo","pmids":["19202076"],"is_preprint":false},{"year":2011,"finding":"A viable hypomorphic allele of Mbtps1 (woodrat) with diminished enzymatic activity limits persistent (but not acute) LCMV infection in an organ/cell-type-specific manner. Analysis of bone marrow-derived dendritic cells from woodrat mice supports their specific role in resolving persistent viral infection, indicating that Mbtps1 activity in dendritic cells is critical for viral persistence. Cleavage of the arenavirus glycoprotein precursor by Mbtps1 is essential for the arenavirus life cycle.","method":"Hypomorphic Mbtps1 allele (woodrat); LCMV persistent infection model; viral titer measurements by organ; bone marrow-derived dendritic cell analysis","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (hypomorphic allele), cell-type-specific epistasis via bone marrow-derived dendritic cells, specific viral titer readout, in vivo","pmids":["21402360"],"is_preprint":false},{"year":2015,"finding":"Conditional deletion of Mbtps1 (cKO) in bone osteocytes leads to an age-related increase in soleus muscle mass (~12%) and contractile force (~30%) in adult slow-twitch muscle, with increased expression of muscle regeneration markers (Pax7, Myog, Myod1, Notch, Myh3) and 6-fold more centralized nuclei characteristic of regenerating muscle. No change in Mbtps1 mRNA or protein was detected in cKO soleus muscle itself, indicating the effect is mediated through bone-muscle cross-talk from osteocytes.","method":"Cre-lox conditional knockout in osteocytes; muscle contractile force measurement; histology (centralized nuclei); qPCR for muscle regeneration markers; microarray gene expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with specific cellular and phenotypic readouts, but mechanistic pathway from osteocyte Mbtps1 deletion to muscle phenotype not fully resolved","pmids":["26719336"],"is_preprint":false},{"year":2012,"finding":"SKI-1/S1P inhibitor PF-429242 blocks HCV genome replication (EC50 = 5.8 μM) and dramatically reduces infectious particle production (EC90 = 4.8 μM) more efficiently than statins, and reduces lipid droplet accumulation in Huh7 cells. This establishes that SKI-1/S1P activity, acting upstream of HMG-CoAR via the SREBP lipogenic pathway, is essential for HCV production.","method":"SKI-1/S1P small molecule inhibitor (PF-429242); HCV replicon and HCVcc (JFH-1) assays; comparison with statins; lipid droplet staining","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with dose-response, comparison with alternative pathway inhibitors, single lab","pmids":["22626636"],"is_preprint":false},{"year":2015,"finding":"SKI-1/S1P inhibitor PF-429242 impairs early steps of HCV infection through two mechanisms: an SREBP/SKI-1/S1P-dependent mechanism involving LDLR and NPC1L1 proteins, and an SREBP-independent mechanism. This confirms SKI-1/S1P as a relevant target at multiple stages of the HCV lifecycle.","method":"PF-429242 pharmacological inhibition; HCV lifecycle assays at early steps; SREBP pathway analysis; LDLR and NPC1L1 expression analysis","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with pathway dissection (SREBP-dependent vs independent), single lab","pmids":["25573299"],"is_preprint":false}],"current_model":"MBTPS1 (SKI-1/S1P) is a Ca2+-dependent subtilisin-like serine protease that undergoes autocatalytic prosegment processing in the ER, localizes predominantly to the Golgi, and cleaves substrates including SREBPs, ATF6, and viral glycoprotein precursors after nonbasic residues; it serves as an essential, non-redundant component of the ATF6-driven unfolded protein response in non-hematopoietic cells, regulates lipid metabolism via the SREBP pathway (relevant to HCV replication), processes arenavirus glycoproteins in dendritic cells to enable persistent viral infection, and mediates bone-to-muscle cross-talk through osteocyte-specific activity."},"narrative":{"mechanistic_narrative":"MBTPS1 (SKI-1/S1P) is a Ca2+-dependent subtilisin-like serine protease that initiates regulated intramembrane proteolysis of membrane-anchored transcription factors and other precursors, thereby coupling proteolytic maturation to lipid metabolism, the unfolded protein response, and viral glycoprotein processing [PMID:10644685, PMID:19202076]. The enzyme matures through multiple sequential autocatalytic prosegment cleavages within the ER, with prosegment fragments retained as tight-binding inhibitors, and cleaves substrates after nonbasic residues using P/P' determinants defined for SREBP-2-like sequences [PMID:10644685]. After maturation it undergoes ectodomain shedding and an internal alternate-translation event (at Met990) to generate membrane-bound stumps that modulate its processing of ATF6; mature and processed forms localize predominantly to the Golgi, traffic to endosomal/lysosomal compartments, and are excluded from the cell surface by a transmembrane-domain trafficking determinant [PMID:17623657]. MBTPS1 is a non-redundant, cell-autonomous activator of the ATF6-dependent UPR in non-hematopoietic cells, where its loss reduces ER chaperones GRP78 and GRP94 and sensitizes to experimental colitis [PMID:19202076]. Through the SREBP lipogenic axis, MBTPS1 activity is required for hepatitis C virus genome replication and infectious particle production, acting upstream of HMG-CoA reductase and through LDLR/NPC1L1-dependent and SREBP-independent routes [PMID:22626636, PMID:25573299], and its cleavage of arenavirus glycoprotein precursors in dendritic cells is essential for persistent viral infection [PMID:21402360]. Osteocyte-specific MBTPS1 also mediates bone-to-muscle cross-talk, with its deletion increasing slow-twitch muscle mass, contractile force, and regeneration markers without altering muscle MBTPS1 expression [PMID:26719336].","teleology":[{"year":2000,"claim":"Established the fundamental enzymology of MBTPS1 — whether it is a bona fide protease and how it selects cleavage sites — by defining it as a Ca2+-dependent subtilisin-like proteinase with autocatalytic prosegment processing and substrate residue requirements.","evidence":"Biochemical characterization in LoVo cells with recombinant enzyme, mass spectrometry cleavage-site mapping, synthetic peptide processing, and site-directed mutagenesis","pmids":["10644685"],"confidence":"High","gaps":["Physiological substrate repertoire beyond SREBP-2 and pro-BDNF mimicking peptides not defined here","No structural model of the catalytic domain","In-cell relevance of prosegment-mediated inhibition not quantified"]},{"year":2007,"claim":"Resolved how the enzyme matures and where it acts by mapping sequential autocatalytic cleavages, ectodomain shedding, an alternate-translation-derived C-terminal fragment, and Golgi-predominant trafficking that feeds back on ATF6 processing.","evidence":"Site-directed mutagenesis, in vitro transcription/translation, N-terminal sequencing, mass spectrometry, and confocal microscopy with deletion analysis","pmids":["17623657"],"confidence":"High","gaps":["Functional role of stumps St-1/St-2 in regulating substrate choice incompletely defined","Mechanism by which the transmembrane domain dictates trafficking not detailed"]},{"year":2009,"claim":"Demonstrated the in vivo, cell-type-specific physiological requirement for MBTPS1 by showing it is non-redundantly needed in non-hematopoietic cells for the ATF6-dependent UPR and protection from colitis.","evidence":"ENU-induced hypomorphic allele, DSS colitis model, GRP78/GRP94 Western blots, and bone marrow chimeras","pmids":["19202076"],"confidence":"High","gaps":["Hypomorphic allele leaves residual activity, so null phenotype not assessed","Direct link between ATF6 cleavage and colitis protection inferred from chaperone levels"]},{"year":2011,"claim":"Connected MBTPS1 protease activity to host control of viral infection by showing dendritic-cell MBTPS1 cleaves arenavirus glycoprotein precursors and is required for persistent, but not acute, LCMV infection.","evidence":"Hypomorphic Mbtps1 allele, LCMV persistent infection model, organ-specific viral titers, and bone marrow-derived dendritic cell analysis","pmids":["21402360"],"confidence":"High","gaps":["Why persistence and not acute infection depends on Mbtps1 not fully explained","Direct biochemical cleavage of arenavirus GP precursor not reconstituted here"]},{"year":2012,"claim":"Showed MBTPS1 enzymatic activity is essential for HCV production via the SREBP lipogenic pathway, identifying it as a pharmacological antiviral target acting upstream of HMG-CoA reductase.","evidence":"PF-429242 inhibitor with dose-response in HCV replicon and HCVcc (JFH-1) assays, comparison with statins, and lipid droplet staining","pmids":["22626636"],"confidence":"Medium","gaps":["Single lab; pharmacological inhibitor specificity not orthogonally confirmed","Direct SREBP processing events in this system not measured"]},{"year":2015,"claim":"Refined MBTPS1's role across the HCV lifecycle by distinguishing an SREBP/LDLR/NPC1L1-dependent contribution to early infection from an SREBP-independent contribution.","evidence":"PF-429242 inhibition with HCV early-step assays and LDLR/NPC1L1 expression analysis","pmids":["25573299"],"confidence":"Medium","gaps":["Molecular basis of the SREBP-independent mechanism unidentified","Single lab, inhibitor-based evidence"]},{"year":2015,"claim":"Revealed a non-cell-autonomous endocrine role by showing osteocyte-specific MBTPS1 deletion enhances slow-twitch muscle mass, force, and regeneration through bone-to-muscle cross-talk.","evidence":"Osteocyte Cre-lox conditional knockout, muscle contractile force measurement, histology of centralized nuclei, qPCR, and microarray","pmids":["26719336"],"confidence":"Medium","gaps":["The osteocyte-derived signaling factor mediating the muscle effect not identified","Relevant MBTPS1 substrate in osteocytes not defined"]},{"year":null,"claim":"The complete physiological substrate repertoire and the structural basis of MBTPS1 substrate selection across its UPR, lipogenic, viral, and endocrine roles remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking active-site to nonbasic-residue specificity","Mediator of osteocyte-to-muscle cross-talk unidentified","SREBP-independent antiviral mechanism uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,6]}],"complexes":[],"partners":["SREBF2","ATF6"],"other_free_text":[]}},"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":"15258915","id":"PMC_15258915","title":"Structural 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proteinase with optimal cleavage activity at pH 6.5. Its prosegment is processed into 26-, 24-, 14-, 10-, and 8-kDa fragments within the ER, some remaining tightly associated with the enzyme. In vitro, recombinant prosegments inhibit SKI-1 activity with Ki ~100–200 nM. The enzyme cleaves substrates including SREBP-2 and pro-BDNF mimicking peptides; mutagenesis of the RRLL(186)-containing prosegment peptide defined key P and P' residues for cleavage.\",\n      \"method\": \"Biochemical characterization in LoVo cells; N-terminal sequencing and mass spectrometry; in vitro enzymatic assay with secreted recombinant SKI-1; synthetic peptide processing; site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified enzyme, mutagenesis of substrate residues, mass spectrometry mapping of cleavage sites, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"10644685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SKI-1/S1P (MBTPS1) undergoes three sequential autocatalytic prosegment processing steps and an ectodomain shedding producing a membrane-bound stump (St-1, aa 954–1052) at KHQKLL(953). A smaller C-terminal fragment St-2 is generated by an internal alternate translation event at Met(990), confirmed by in vitro transcription/translation; M990A/I/L mutations abolished St-2 generation. Confocal microscopy showed that membrane-bound SKI-1, St-1, and St-2 localize predominantly to the Golgi and can traffic to endosomal/lysosomal compartments but not to the cell surface; the transmembrane domain determines this trafficking. St-1 and St-2 affect ATF6 processing by SKI-1.\",\n      \"method\": \"Site-directed mutagenesis; in vitro transcription/translation assay; N-terminal sequencing; mass spectrometry; confocal microscopy; deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis validated by in vitro transcription/translation, subcellular localization by confocal microscopy with functional consequence (ATF6 processing), multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"17623657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"An ENU-induced hypomorphic missense mutation in Mbtps1 causes enhanced susceptibility to DSS-induced colitis. S1P (MBTPS1) has a non-redundant function in the ATF6-dependent unfolded protein response (UPR); woodrat mice with diminished S1P activity show reduced levels of ER chaperones GRP78 (BiP) and GRP94 in the colon upon DSS treatment. 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; DSS colitis model; Western blot for GRP78/GRP94; bone marrow chimeric mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via hypomorphic allele, bone marrow chimera dissection of cell-type requirement, specific molecular readout (chaperone levels), replicated in vivo\",\n      \"pmids\": [\"19202076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A viable hypomorphic allele of Mbtps1 (woodrat) with diminished enzymatic activity limits persistent (but not acute) LCMV infection in an organ/cell-type-specific manner. Analysis of bone marrow-derived dendritic cells from woodrat mice supports their specific role in resolving persistent viral infection, indicating that Mbtps1 activity in dendritic cells is critical for viral persistence. Cleavage of the arenavirus glycoprotein precursor by Mbtps1 is essential for the arenavirus life cycle.\",\n      \"method\": \"Hypomorphic Mbtps1 allele (woodrat); LCMV persistent infection model; viral titer measurements by organ; bone marrow-derived dendritic cell analysis\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (hypomorphic allele), cell-type-specific epistasis via bone marrow-derived dendritic cells, specific viral titer readout, in vivo\",\n      \"pmids\": [\"21402360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional deletion of Mbtps1 (cKO) in bone osteocytes leads to an age-related increase in soleus muscle mass (~12%) and contractile force (~30%) in adult slow-twitch muscle, with increased expression of muscle regeneration markers (Pax7, Myog, Myod1, Notch, Myh3) and 6-fold more centralized nuclei characteristic of regenerating muscle. No change in Mbtps1 mRNA or protein was detected in cKO soleus muscle itself, indicating the effect is mediated through bone-muscle cross-talk from osteocytes.\",\n      \"method\": \"Cre-lox conditional knockout in osteocytes; muscle contractile force measurement; histology (centralized nuclei); qPCR for muscle regeneration markers; microarray gene expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with specific cellular and phenotypic readouts, but mechanistic pathway from osteocyte Mbtps1 deletion to muscle phenotype not fully resolved\",\n      \"pmids\": [\"26719336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SKI-1/S1P inhibitor PF-429242 blocks HCV genome replication (EC50 = 5.8 μM) and dramatically reduces infectious particle production (EC90 = 4.8 μM) more efficiently than statins, and reduces lipid droplet accumulation in Huh7 cells. This establishes that SKI-1/S1P activity, acting upstream of HMG-CoAR via the SREBP lipogenic pathway, is essential for HCV production.\",\n      \"method\": \"SKI-1/S1P small molecule inhibitor (PF-429242); HCV replicon and HCVcc (JFH-1) assays; comparison with statins; lipid droplet staining\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with dose-response, comparison with alternative pathway inhibitors, single lab\",\n      \"pmids\": [\"22626636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SKI-1/S1P inhibitor PF-429242 impairs early steps of HCV infection through two mechanisms: an SREBP/SKI-1/S1P-dependent mechanism involving LDLR and NPC1L1 proteins, and an SREBP-independent mechanism. This confirms SKI-1/S1P as a relevant target at multiple stages of the HCV lifecycle.\",\n      \"method\": \"PF-429242 pharmacological inhibition; HCV lifecycle assays at early steps; SREBP pathway analysis; LDLR and NPC1L1 expression analysis\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with pathway dissection (SREBP-dependent vs independent), single lab\",\n      \"pmids\": [\"25573299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBTPS1 (SKI-1/S1P) is a Ca2+-dependent subtilisin-like serine protease that undergoes autocatalytic prosegment processing in the ER, localizes predominantly to the Golgi, and cleaves substrates including SREBPs, ATF6, and viral glycoprotein precursors after nonbasic residues; it serves as an essential, non-redundant component of the ATF6-driven unfolded protein response in non-hematopoietic cells, regulates lipid metabolism via the SREBP pathway (relevant to HCV replication), processes arenavirus glycoproteins in dendritic cells to enable persistent viral infection, and mediates bone-to-muscle cross-talk through osteocyte-specific activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MBTPS1 (SKI-1/S1P) is a Ca2+-dependent subtilisin-like serine protease that initiates regulated intramembrane proteolysis of membrane-anchored transcription factors and other precursors, thereby coupling proteolytic maturation to lipid metabolism, the unfolded protein response, and viral glycoprotein processing [#0, #2]. The enzyme matures through multiple sequential autocatalytic prosegment cleavages within the ER, with prosegment fragments retained as tight-binding inhibitors, and cleaves substrates after nonbasic residues using P/P' determinants defined for SREBP-2-like sequences [#0]. After maturation it undergoes ectodomain shedding and an internal alternate-translation event (at Met990) to generate membrane-bound stumps that modulate its processing of ATF6; mature and processed forms localize predominantly to the Golgi, traffic to endosomal/lysosomal compartments, and are excluded from the cell surface by a transmembrane-domain trafficking determinant [#1]. MBTPS1 is a non-redundant, cell-autonomous activator of the ATF6-dependent UPR in non-hematopoietic cells, where its loss reduces ER chaperones GRP78 and GRP94 and sensitizes to experimental colitis [#2]. Through the SREBP lipogenic axis, MBTPS1 activity is required for hepatitis C virus genome replication and infectious particle production, acting upstream of HMG-CoA reductase and through LDLR/NPC1L1-dependent and SREBP-independent routes [#5, #6], and its cleavage of arenavirus glycoprotein precursors in dendritic cells is essential for persistent viral infection [#3]. Osteocyte-specific MBTPS1 also mediates bone-to-muscle cross-talk, with its deletion increasing slow-twitch muscle mass, contractile force, and regeneration markers without altering muscle MBTPS1 expression [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the fundamental enzymology of MBTPS1 — whether it is a bona fide protease and how it selects cleavage sites — by defining it as a Ca2+-dependent subtilisin-like proteinase with autocatalytic prosegment processing and substrate residue requirements.\",\n      \"evidence\": \"Biochemical characterization in LoVo cells with recombinant enzyme, mass spectrometry cleavage-site mapping, synthetic peptide processing, and site-directed mutagenesis\",\n      \"pmids\": [\"10644685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological substrate repertoire beyond SREBP-2 and pro-BDNF mimicking peptides not defined here\",\n        \"No structural model of the catalytic domain\",\n        \"In-cell relevance of prosegment-mediated inhibition not quantified\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved how the enzyme matures and where it acts by mapping sequential autocatalytic cleavages, ectodomain shedding, an alternate-translation-derived C-terminal fragment, and Golgi-predominant trafficking that feeds back on ATF6 processing.\",\n      \"evidence\": \"Site-directed mutagenesis, in vitro transcription/translation, N-terminal sequencing, mass spectrometry, and confocal microscopy with deletion analysis\",\n      \"pmids\": [\"17623657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional role of stumps St-1/St-2 in regulating substrate choice incompletely defined\",\n        \"Mechanism by which the transmembrane domain dictates trafficking not detailed\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated the in vivo, cell-type-specific physiological requirement for MBTPS1 by showing it is non-redundantly needed in non-hematopoietic cells for the ATF6-dependent UPR and protection from colitis.\",\n      \"evidence\": \"ENU-induced hypomorphic allele, DSS colitis model, GRP78/GRP94 Western blots, and bone marrow chimeras\",\n      \"pmids\": [\"19202076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Hypomorphic allele leaves residual activity, so null phenotype not assessed\",\n        \"Direct link between ATF6 cleavage and colitis protection inferred from chaperone levels\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected MBTPS1 protease activity to host control of viral infection by showing dendritic-cell MBTPS1 cleaves arenavirus glycoprotein precursors and is required for persistent, but not acute, LCMV infection.\",\n      \"evidence\": \"Hypomorphic Mbtps1 allele, LCMV persistent infection model, organ-specific viral titers, and bone marrow-derived dendritic cell analysis\",\n      \"pmids\": [\"21402360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why persistence and not acute infection depends on Mbtps1 not fully explained\",\n        \"Direct biochemical cleavage of arenavirus GP precursor not reconstituted here\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed MBTPS1 enzymatic activity is essential for HCV production via the SREBP lipogenic pathway, identifying it as a pharmacological antiviral target acting upstream of HMG-CoA reductase.\",\n      \"evidence\": \"PF-429242 inhibitor with dose-response in HCV replicon and HCVcc (JFH-1) assays, comparison with statins, and lipid droplet staining\",\n      \"pmids\": [\"22626636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; pharmacological inhibitor specificity not orthogonally confirmed\",\n        \"Direct SREBP processing events in this system not measured\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined MBTPS1's role across the HCV lifecycle by distinguishing an SREBP/LDLR/NPC1L1-dependent contribution to early infection from an SREBP-independent contribution.\",\n      \"evidence\": \"PF-429242 inhibition with HCV early-step assays and LDLR/NPC1L1 expression analysis\",\n      \"pmids\": [\"25573299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of the SREBP-independent mechanism unidentified\",\n        \"Single lab, inhibitor-based evidence\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-cell-autonomous endocrine role by showing osteocyte-specific MBTPS1 deletion enhances slow-twitch muscle mass, force, and regeneration through bone-to-muscle cross-talk.\",\n      \"evidence\": \"Osteocyte Cre-lox conditional knockout, muscle contractile force measurement, histology of centralized nuclei, qPCR, and microarray\",\n      \"pmids\": [\"26719336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The osteocyte-derived signaling factor mediating the muscle effect not identified\",\n        \"Relevant MBTPS1 substrate in osteocytes not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The complete physiological substrate repertoire and the structural basis of MBTPS1 substrate selection across its UPR, lipogenic, viral, and endocrine roles remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying structural model linking active-site to nonbasic-residue specificity\",\n        \"Mediator of osteocyte-to-muscle cross-talk unidentified\",\n        \"SREBP-independent antiviral mechanism uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008233\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SREBF2\", \"ATF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}