{"gene":"MBTPS2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1997,"finding":"MBTPS2 (S2P) encodes a polytopic membrane-bound zinc metalloprotease required for intramembrane proteolysis of sterol regulatory element-binding proteins (SREBPs) at Site-2, releasing their active NH2-terminal transcriptional domains from membranes. Mutation of the HEXXH putative zinc-binding residues abolishes S2P activity.","method":"Complementation cloning of mutant CHO cells deficient in Site-2 cleavage; active-site mutagenesis of HEXXH motif","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — functional complementation plus active-site mutagenesis establishing catalytic mechanism; foundational paper with 392 citations","pmids":["9659902"],"is_preprint":false},{"year":1999,"finding":"S2P has a membrane topology in the ER where both NH2 and COOH termini face the cytosol, all three long hydrophilic loops project into the lumen, and the catalytic HEIGH sequence and Asp467 (third zinc-coordinating residue) are located within hydrophobic/transmembrane segments, positioning the active site within the membrane bilayer to cleave SREBP transmembrane helices.","method":"Protease protection assays and glycosylation site mapping in ER membranes; mutagenesis of Asp467","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods (protease protection, glycosylation mapping, mutagenesis) defining active-site topology","pmids":["10419520"],"is_preprint":false},{"year":2002,"finding":"S2P-mediated cleavage of ER-localized ATF6 generates an N-terminal fragment required for UPR transcriptional activation; S2P deficiency in CHO cells abolishes ATF6 processing and blocks induction of UPR target genes including XBP1 mRNA upregulation, demonstrating S2P's role in the ATF6 branch of the unfolded protein response.","method":"S2P-deficient CHO cell complementation; UPR reporter gene assays; ATF6 cleavage and nuclear translocation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function in defined cell lines with multiple molecular readouts; replicated across labs; 861 citations","pmids":["11850408"],"is_preprint":false},{"year":2009,"finding":"Missense mutations in MBTPS2 cause IFAP syndrome by reducing the zinc metalloprotease activity required for SREBP cleavage and ER stress response; wild-type MBTPS2 complements protease-deficient CHO M19 cells, restoring SRE-reporter induction and cholesterol-independent growth, while five patient-derived mutations impair these functions to varying degrees correlating with clinical severity.","method":"Complementation of CHO M19 protease-deficient cells; SRE-regulated reporter gene assay; growth in cholesterol/lipid-free media; transient and stable transfection","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — functional complementation with multiple patient mutations correlated to activity levels and clinical severity","pmids":["19361614"],"is_preprint":false},{"year":2010,"finding":"The MBTPS2 p.Asn508Ser mutation causes KFSD by reducing MBTPS2-dependent sterol responsiveness by approximately half, as shown by in vitro functional expression studies in protease-deficient cells measuring SREBP pathway activity.","method":"In vitro functional expression in protease-deficient cells; sterol-responsive reporter assay","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay in complementation system, single lab","pmids":["20672378"],"is_preprint":false},{"year":2013,"finding":"Patient-derived MBTPS2 missense mutations cluster in transmembrane domains, and those near the active site cause greater loss of enzymatic function (as measured by cholesterol-free cell growth and sterol-responsive transcription assays) and more severe clinical phenotypes, establishing a genotype-phenotype correlation linked to catalytic activity.","method":"Cell growth assays in lipid-free media; sterol-responsive transcription assays; mutational analysis of 11 variants from 13 families","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mutations functionally characterized with two orthogonal assays, moderate evidence","pmids":["23316014"],"is_preprint":false},{"year":2016,"finding":"Structural analysis of intramembrane proteases including S2P-family metalloproteases reveals distinct protein folds and active-site configurations, with structural data and structure-guided biochemical analyses shedding light on mechanisms of water access and substrate entry into the hydrophobic active site.","method":"Review of crystal and cryo-EM structures with structure-guided biochemical analyses","journal":"Current opinion in structural biology","confidence":"Medium","confidence_rationale":"Tier 1 — structural data reviewed with biochemical validation; review article, moderate confidence for MBTPS2 specifically","pmids":["26811996"],"is_preprint":false},{"year":2017,"finding":"MBTPS2 directly regulates the TRPV3 gene regulatory region, and cells transfected with mutant MBTPS2 show increased cell death compared to wild-type, suggesting a regulatory axis between MBTPS2 and TRPV3 that may contribute to overlapping IFAP/Olmsted syndrome features.","method":"Luciferase reporter assays for TRPV3 promoter activity; cell viability assays with wild-type vs. mutant MBTPS2 transfection","journal":"Archives of dermatological research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, reporter assay only, limited mechanistic follow-up","pmids":["28717930"],"is_preprint":false},{"year":2021,"finding":"MBTPS2 acts within the ATF6α/S1P/S2P signaling pathway to mediate ER stress-induced hippocampal neuronal apoptosis; pharmacological inhibition of the ATF6α pathway reduces S2P expression and downstream CHOP and caspase-12 induction along with neuronal apoptosis in a PTSD rat model.","method":"Western blotting, qRT-PCR, immunohistochemistry, TUNEL staining in SPS rat model with ATF6α pathway inhibitor AEBSF","journal":"Journal of molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 — pharmacological inhibitor used rather than direct MBTPS2 manipulation; indirect pathway evidence","pmids":["33738762"],"is_preprint":false},{"year":2021,"finding":"MBTPS2 knockdown in LNCaP prostate cancer cells impairs SREBP-dependent cholesterol synthesis and uptake and reduces expression of key fatty acid synthesis regulators FASN and ACACA, demonstrating that MBTPS2 acts through SREBP signaling to regulate lipogenesis and cholesterol metabolism in cancer cells.","method":"siRNA knockdown; RNA-Seq; qPCR pathway validation; Filipin III staining for cholesterol","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNA-Seq, qPCR, cholesterol staining) in direct KD experiment, single lab","pmids":["36991255"],"is_preprint":false},{"year":2021,"finding":"A novel MBTPS2 missense variant (p.Val256Leu) causing BRESHECK syndrome impairs cell growth in cholesterol-depleted media, attenuates SREBP pathway activation, and fails to activate the ER stress response pathway, confirming that MBTPS2 function is required for both sterol-regulated transcription and ER stress signaling.","method":"In vitro modeling: cell growth in cholesterol-depleted media; SREBP reporter assay; ER stress response assay","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal functional assays in complementation system, single lab","pmids":["34655156"],"is_preprint":false},{"year":2021,"finding":"MBTPS2 overexpression exacerbates albuminuria and promotes ER stress and renal damage in a streptozotocin-induced type 1 diabetic nephropathy mouse model, while knockdown attenuates albuminuria; chemical chaperone reduction of ER stress rescues MBTPS2-exacerbated renal damage, linking MBTPS2 function to ER stress regulation in kidney.","method":"In vivo MBTPS2 overexpression and knockdown in STZ mouse model; albuminuria measurement; ER stress markers; 4-PBA rescue experiment","journal":"Archives of physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function in vivo with pharmacological rescue, single lab","pmids":["32255378"],"is_preprint":false},{"year":2023,"finding":"The lipogenesis signal cascade Scap-SREBP1-S1P/S2P orchestrates NF-κB homeostasis and spatiotemporal activation: Scap transports a Scap-SREBP1-IκBα supercomplex from the ER to the Golgi where MBTPS2 (S2P) cleaves SREBP1, liberating IκBα for IKK-mediated phosphorylation and NF-κB activation in response to LPS; inhibition of S2P diminishes LPS-induced NF-κB activation.","method":"Co-IP to identify Scap-SREBP1-IκBα complex; S2P inhibitor experiments; Scap/SREBP1 KO cells; LPS stimulation assays measuring NF-κB activation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus pharmacological inhibition plus genetic KO with defined molecular readout, single lab","pmids":["37267109"],"is_preprint":false},{"year":2021,"finding":"MBTPS2 is required for activating transcription factors involved in bone (OASIS) and cartilage development (BBF2H7), ER stress response (ATF6), and lipid metabolism (SREBP) via regulated intramembrane proteolysis; MBTPS2-OI patient fibroblasts show stronger downregulation of SREBP-dependent genes and altered fatty acid abundance compared to MBTPS2-IFAP/KFSD fibroblasts.","method":"RNA-sequencing transcriptome profiling of patient-derived fibroblasts; fatty acid quantification by GC-MS","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-Seq plus metabolomic profiling in patient-derived cells with comparison across disease alleles","pmids":["34093655"],"is_preprint":false},{"year":2023,"finding":"Heterozygous Mbtps2 knock-in (N455S) and knock-out mice show osteochondral abnormalities including thinned subchondral bone, altered osteocyte interconnectivity, and thickened articular cartilage with chondrocyte clustering; hemizygous loss-of-function leads to embryonic lethality in male mice, establishing an in vivo requirement for MBTPS2 in maintaining bone and cartilage homeostasis.","method":"Knock-in and knock-out mouse models; skeletal histomorphometry; microCT; confocal microscopy of lacunocanalicular network","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — two independent mouse models with defined skeletal phenotypes and multiple imaging modalities","pmids":["37797712"],"is_preprint":false},{"year":2016,"finding":"An intronic MBTPS2 variant (c.1437+4T>C) in horses causes partial skipping of exon 10, producing an aberrant MBTPS2 transcript and brindle coat phenotype, demonstrating that MBTPS2 function in skin requires correct splicing and that loss of MBTPS2 activity affects skin/hair follicle biology.","method":"Whole genome sequencing; RT-PCR transcript analysis; cosegregation analysis in a horse family","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — molecular demonstration of splice defect with cosegregation in an animal model relevant to mammalian MBTPS2 function","pmids":["27449517"],"is_preprint":false}],"current_model":"MBTPS2 (site-2 protease, S2P) is a Golgi/ER membrane-embedded zinc metalloprotease with its active site (HEXXH motif and Asp467) positioned within the membrane bilayer, where it performs regulated intramembrane proteolysis of multiple substrate transcription factors—including SREBPs (regulating cholesterol and fatty acid homeostasis), ATF6 (mediating the ER unfolded protein response), OASIS, and BBF2H7—by cleaving their first transmembrane domain after a priming Site-1 protease cut, releasing active N-terminal fragments to the nucleus; it also participates in NF-κB spatial activation by cleaving SREBP1 at the Golgi to liberate IκBα, and loss-of-function mutations cause a spectrum of X-linked human diseases affecting skin, bone, and other tissues proportional to the degree of enzymatic impairment."},"narrative":{"teleology":[{"year":1997,"claim":"The identity of the protease responsible for Site-2 cleavage of SREBPs was unknown; complementation cloning of mutant CHO cells identified MBTPS2 as a membrane-bound zinc metalloprotease whose HEXXH motif is essential for liberating SREBP transcriptional domains, establishing S2P as a novel intramembrane protease.","evidence":"Complementation cloning in CHO cells deficient in Site-2 cleavage; HEXXH active-site mutagenesis","pmids":["9659902"],"confidence":"High","gaps":["Exact topology and position of the active site within the membrane not yet resolved","Substrate range beyond SREBPs unknown","No structural data for S2P"]},{"year":1999,"claim":"How a metalloprotease active site could function within a hydrophobic membrane was unclear; topology mapping showed the HEIGH catalytic sequence and Asp467 reside within transmembrane segments with luminal hydrophilic loops, establishing that S2P catalyzes proteolysis inside the lipid bilayer.","evidence":"Protease protection assays, glycosylation site mapping in ER membranes, and Asp467 mutagenesis","pmids":["10419520"],"confidence":"High","gaps":["Mechanism of water access to the intramembrane active site unresolved","Structural basis for substrate entry into the active site unknown"]},{"year":2002,"claim":"Whether S2P cleaved substrates beyond SREBPs was unknown; demonstration that S2P is required for ATF6 processing during ER stress expanded S2P's role from lipid homeostasis to the unfolded protein response.","evidence":"S2P-deficient CHO cell complementation; UPR reporter assays; ATF6 cleavage and nuclear translocation assays","pmids":["11850408"],"confidence":"High","gaps":["Structural basis for dual substrate recognition (SREBP vs. ATF6) not determined","Other potential ER stress-related substrates not yet identified"]},{"year":2009,"claim":"The molecular basis of IFAP syndrome was unknown; identification of MBTPS2 missense mutations that impair SREBP cleavage to varying degrees, with activity levels correlating to clinical severity, established MBTPS2 as the causative gene and linked enzymatic function to disease.","evidence":"Complementation of CHO M19 cells with five patient-derived MBTPS2 mutations; SRE-reporter and cholesterol-free growth assays","pmids":["19361614"],"confidence":"High","gaps":["Pathogenic mechanisms in affected tissues (skin, hair follicles) not directly examined","Relative contribution of impaired SREBP vs. ATF6 processing to clinical features unclear"]},{"year":2010,"claim":"Whether distinct MBTPS2 mutations cause allelic skin disorders was unclear; the p.Asn508Ser mutation was shown to reduce sterol responsiveness by approximately half, causing KFSD and extending the allelic disease spectrum.","evidence":"Functional expression in protease-deficient cells; sterol-responsive reporter assay","pmids":["20672378"],"confidence":"Medium","gaps":["Whether Asn508Ser affects ATF6 or other substrate processing not tested","Single lab finding"]},{"year":2013,"claim":"The structural basis for genotype–phenotype correlations was unclear; systematic functional analysis of 11 patient variants showed that mutations clustering near the transmembrane active site cause greater enzymatic loss and more severe phenotypes, establishing a quantitative structure–function–disease relationship.","evidence":"Cell growth in lipid-free media and sterol-responsive transcription assays for 11 MBTPS2 variants from 13 families","pmids":["23316014"],"confidence":"Medium","gaps":["No high-resolution structure of human S2P to map mutations precisely","Functional consequences for non-SREBP substrates not assessed"]},{"year":2016,"claim":"Structural principles governing intramembrane proteolysis by S2P-family metalloproteases—including water access and substrate entry mechanisms—were partially elucidated through crystal and cryo-EM structures of family members.","evidence":"Review of crystal/cryo-EM structures with structure-guided biochemical analyses","pmids":["26811996"],"confidence":"Medium","gaps":["High-resolution structure of human MBTPS2 itself not available","Substrate-bound structure not determined"]},{"year":2021,"claim":"MBTPS2's role in bone and cartilage development was confirmed: patient fibroblasts with OI-causing mutations show stronger downregulation of SREBP targets and altered fatty acid profiles than IFAP/KFSD alleles, and MBTPS2 processes OASIS and BBF2H7 transcription factors involved in skeletal tissue formation.","evidence":"RNA-Seq transcriptome profiling and GC-MS fatty acid quantification in patient-derived fibroblasts across disease alleles","pmids":["34093655"],"confidence":"Medium","gaps":["Direct cleavage of OASIS and BBF2H7 by MBTPS2 not demonstrated in this study with reconstituted assays","Mechanism linking altered fatty acid profiles to skeletal phenotype unclear"]},{"year":2021,"claim":"BRESHECK syndrome was linked to MBTPS2: a novel p.Val256Leu variant impairs both SREBP pathway activation and ER stress response, confirming that severe loss of dual pathway activity underlies the most severe MBTPS2-associated phenotype.","evidence":"Cell growth in cholesterol-depleted media; SREBP reporter assay; ER stress response assay in complementation system","pmids":["34655156"],"confidence":"Medium","gaps":["Single lab; whether this variant affects OASIS/BBF2H7 processing not tested","In vivo validation of BRESHECK mechanisms lacking"]},{"year":2021,"claim":"MBTPS2 knockdown in prostate cancer cells confirmed that MBTPS2 acts through SREBP signaling to regulate cholesterol synthesis/uptake and fatty acid synthesis gene expression (FASN, ACACA), demonstrating functional relevance in cancer cell lipogenesis.","evidence":"siRNA knockdown in LNCaP cells; RNA-Seq; qPCR; Filipin III cholesterol staining","pmids":["36991255"],"confidence":"Medium","gaps":["Whether MBTPS2 is essential for tumor growth in vivo not tested","Contribution of ATF6 branch vs. SREBP branch in cancer context not dissected"]},{"year":2023,"claim":"A previously unrecognized link between lipogenesis signaling and innate immunity was established: MBTPS2 cleaves SREBP1 at the Golgi within a Scap–SREBP1–IκBα supercomplex, liberating IκBα for IKK phosphorylation and NF-κB activation upon LPS stimulation.","evidence":"Co-IP identifying Scap–SREBP1–IκBα complex; S2P inhibitor and Scap/SREBP1 KO cells; LPS-stimulated NF-κB activation assays","pmids":["37267109"],"confidence":"Medium","gaps":["Reciprocal validation of the supercomplex by independent methods (e.g., size-exclusion chromatography) not reported","In vivo relevance for innate immune responses not demonstrated","Whether other S2P substrates contribute to NF-κB regulation unclear"]},{"year":2023,"claim":"In vivo skeletal requirement for MBTPS2 was established: heterozygous Mbtps2 knock-in (N455S) and knockout mice exhibit osteochondral abnormalities, while hemizygous males show embryonic lethality, confirming essentiality for bone and cartilage homeostasis.","evidence":"Knock-in and knockout mouse models; skeletal histomorphometry; microCT; confocal imaging of lacunocanalicular network","pmids":["37797712"],"confidence":"Medium","gaps":["Molecular substrates responsible for skeletal phenotype in vivo not identified","Whether ER stress or SREBP pathway impairment is the primary driver of skeletal defects not resolved"]},{"year":null,"claim":"Key unresolved questions include: the high-resolution structure of human MBTPS2, the mechanism by which it selects among multiple substrates, the relative contributions of impaired SREBP vs. ATF6 vs. OASIS/BBF2H7 processing to each clinical phenotype, and whether MBTPS2-dependent NF-κB activation is physiologically relevant in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of human MBTPS2","Substrate selectivity mechanism unknown","Relative pathway contributions to distinct tissue phenotypes not dissected in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,12]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,4,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,10]}],"complexes":[],"partners":["SREBF1","SREBF2","ATF6","MBTPS1","SCAP","NFKBIA"],"other_free_text":[]},"mechanistic_narrative":"MBTPS2 (Site-2 Protease, S2P) is a polytopic membrane-embedded zinc metalloprotease that performs regulated intramembrane proteolysis of multiple transcription factor substrates—including SREBPs, ATF6, OASIS, and BBF2H7—thereby controlling cholesterol/fatty acid homeostasis, the ER unfolded protein response, and bone/cartilage development [PMID:9659902, PMID:11850408, PMID:34093655]. Its HEXXH zinc-binding motif and Asp467 residue are positioned within transmembrane segments, placing the catalytic center inside the lipid bilayer to cleave substrate transmembrane helices after priming by Site-1 protease [PMID:10419520]. MBTPS2 also participates in NF-κB spatial activation by cleaving SREBP1 at the Golgi within a Scap–SREBP1–IκBα supercomplex, liberating IκBα for IKK-mediated phosphorylation [PMID:37267109]. Loss-of-function mutations in MBTPS2 cause a spectrum of X-linked human disorders—including IFAP syndrome, KFSD, BRESHECK syndrome, and osteogenesis imperfecta—with clinical severity correlating to the degree of residual enzymatic activity [PMID:19361614, PMID:23316014, PMID:34655156]."},"prefetch_data":{"uniprot":{"accession":"O43462","full_name":"Membrane-bound transcription factor site-2 protease","aliases":["Endopeptidase S2P","Sterol regulatory element-binding proteins intramembrane protease","SREBPs intramembrane protease"],"length_aa":519,"mass_kda":57.4,"function":"Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:10805775, PubMed:11163209). Catalyzes the second step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs within the first transmembrane segment, thereby releasing the N-terminal segment with a portion of the transmembrane segment attached (PubMed:10805775, PubMed:27380894, PubMed:9659902). Mature N-terminal SREBP fragments shuttle to the nucleus and activate gene transcription (PubMed:10805775, PubMed:27380894, PubMed:9659902). Also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:11163209). Involved in intramembrane proteolysis during bone formation (PubMed:27380894). In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the second step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression (PubMed:16417584)","subcellular_location":"Membrane; Cytoplasm; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/O43462/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MBTPS2","classification":"Common Essential","n_dependent_lines":794,"n_total_lines":1208,"dependency_fraction":0.6572847682119205},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MBTPS2","total_profiled":1310},"omim":[{"mim_id":"614594","title":"OLMSTED SYNDROME 1; OLMS1","url":"https://www.omim.org/entry/614594"},{"mim_id":"611998","title":"cAMP RESPONSE ELEMENT-BINDING PROTEIN 3-LIKE 3; CREB3L3","url":"https://www.omim.org/entry/611998"},{"mim_id":"313020","title":"SPERMIDINE/SPERMINE N1-ACETYLTRANSFERASE 1; SAT1","url":"https://www.omim.org/entry/313020"},{"mim_id":"308800","title":"KERATOSIS FOLLICULARIS SPINULOSA DECALVANS, X-LINKED; KFSDX","url":"https://www.omim.org/entry/308800"},{"mim_id":"308205","title":"IFAP SYNDROME 1, WITH OR WITHOUT BRESHECK SYNDROME; IFAP1","url":"https://www.omim.org/entry/308205"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MBTPS2"},"hgnc":{"alias_symbol":["S2P"],"prev_symbol":["KFSD"]},"alphafold":{"accession":"O43462","domains":[{"cath_id":"-","chopping":"2-48","consensus_level":"medium","plddt":91.9632,"start":2,"end":48},{"cath_id":"-","chopping":"67-102_143-245_444-519","consensus_level":"high","plddt":92.1968,"start":67,"end":519},{"cath_id":"-","chopping":"255-429","consensus_level":"medium","plddt":89.0856,"start":255,"end":429}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43462","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43462-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43462-F1-predicted_aligned_error_v6.png","plddt_mean":87.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MBTPS2","jax_strain_url":"https://www.jax.org/strain/search?query=MBTPS2"},"sequence":{"accession":"O43462","fasta_url":"https://rest.uniprot.org/uniprotkb/O43462.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43462/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43462"}},"corpus_meta":[{"pmid":"11850408","id":"PMC_11850408","title":"IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response.","date":"2002","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/11850408","citation_count":861,"is_preprint":false},{"pmid":"9659902","id":"PMC_9659902","title":"Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs.","date":"1997","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9659902","citation_count":392,"is_preprint":false},{"pmid":"19361614","id":"PMC_19361614","title":"IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19361614","citation_count":115,"is_preprint":false},{"pmid":"34655522","id":"PMC_34655522","title":"Safety and immunogenicity of CpG 1018 and aluminium hydroxide-adjuvanted SARS-CoV-2 S-2P protein vaccine MVC-COV1901: interim results of a large-scale, double-blind, randomised, placebo-controlled phase 2 trial in Taiwan.","date":"2021","source":"The Lancet. 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Mutation of the HEXXH putative zinc-binding residues abolishes S2P activity.\",\n      \"method\": \"Complementation cloning of mutant CHO cells deficient in Site-2 cleavage; active-site mutagenesis of HEXXH motif\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional complementation plus active-site mutagenesis establishing catalytic mechanism; foundational paper with 392 citations\",\n      \"pmids\": [\"9659902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"S2P has a membrane topology in the ER where both NH2 and COOH termini face the cytosol, all three long hydrophilic loops project into the lumen, and the catalytic HEIGH sequence and Asp467 (third zinc-coordinating residue) are located within hydrophobic/transmembrane segments, positioning the active site within the membrane bilayer to cleave SREBP transmembrane helices.\",\n      \"method\": \"Protease protection assays and glycosylation site mapping in ER membranes; mutagenesis of Asp467\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods (protease protection, glycosylation mapping, mutagenesis) defining active-site topology\",\n      \"pmids\": [\"10419520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"S2P-mediated cleavage of ER-localized ATF6 generates an N-terminal fragment required for UPR transcriptional activation; S2P deficiency in CHO cells abolishes ATF6 processing and blocks induction of UPR target genes including XBP1 mRNA upregulation, demonstrating S2P's role in the ATF6 branch of the unfolded protein response.\",\n      \"method\": \"S2P-deficient CHO cell complementation; UPR reporter gene assays; ATF6 cleavage and nuclear translocation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in defined cell lines with multiple molecular readouts; replicated across labs; 861 citations\",\n      \"pmids\": [\"11850408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Missense mutations in MBTPS2 cause IFAP syndrome by reducing the zinc metalloprotease activity required for SREBP cleavage and ER stress response; wild-type MBTPS2 complements protease-deficient CHO M19 cells, restoring SRE-reporter induction and cholesterol-independent growth, while five patient-derived mutations impair these functions to varying degrees correlating with clinical severity.\",\n      \"method\": \"Complementation of CHO M19 protease-deficient cells; SRE-regulated reporter gene assay; growth in cholesterol/lipid-free media; transient and stable transfection\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional complementation with multiple patient mutations correlated to activity levels and clinical severity\",\n      \"pmids\": [\"19361614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The MBTPS2 p.Asn508Ser mutation causes KFSD by reducing MBTPS2-dependent sterol responsiveness by approximately half, as shown by in vitro functional expression studies in protease-deficient cells measuring SREBP pathway activity.\",\n      \"method\": \"In vitro functional expression in protease-deficient cells; sterol-responsive reporter assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay in complementation system, single lab\",\n      \"pmids\": [\"20672378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Patient-derived MBTPS2 missense mutations cluster in transmembrane domains, and those near the active site cause greater loss of enzymatic function (as measured by cholesterol-free cell growth and sterol-responsive transcription assays) and more severe clinical phenotypes, establishing a genotype-phenotype correlation linked to catalytic activity.\",\n      \"method\": \"Cell growth assays in lipid-free media; sterol-responsive transcription assays; mutational analysis of 11 variants from 13 families\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mutations functionally characterized with two orthogonal assays, moderate evidence\",\n      \"pmids\": [\"23316014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Structural analysis of intramembrane proteases including S2P-family metalloproteases reveals distinct protein folds and active-site configurations, with structural data and structure-guided biochemical analyses shedding light on mechanisms of water access and substrate entry into the hydrophobic active site.\",\n      \"method\": \"Review of crystal and cryo-EM structures with structure-guided biochemical analyses\",\n      \"journal\": \"Current opinion in structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural data reviewed with biochemical validation; review article, moderate confidence for MBTPS2 specifically\",\n      \"pmids\": [\"26811996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MBTPS2 directly regulates the TRPV3 gene regulatory region, and cells transfected with mutant MBTPS2 show increased cell death compared to wild-type, suggesting a regulatory axis between MBTPS2 and TRPV3 that may contribute to overlapping IFAP/Olmsted syndrome features.\",\n      \"method\": \"Luciferase reporter assays for TRPV3 promoter activity; cell viability assays with wild-type vs. mutant MBTPS2 transfection\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, reporter assay only, limited mechanistic follow-up\",\n      \"pmids\": [\"28717930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBTPS2 acts within the ATF6α/S1P/S2P signaling pathway to mediate ER stress-induced hippocampal neuronal apoptosis; pharmacological inhibition of the ATF6α pathway reduces S2P expression and downstream CHOP and caspase-12 induction along with neuronal apoptosis in a PTSD rat model.\",\n      \"method\": \"Western blotting, qRT-PCR, immunohistochemistry, TUNEL staining in SPS rat model with ATF6α pathway inhibitor AEBSF\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibitor used rather than direct MBTPS2 manipulation; indirect pathway evidence\",\n      \"pmids\": [\"33738762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBTPS2 knockdown in LNCaP prostate cancer cells impairs SREBP-dependent cholesterol synthesis and uptake and reduces expression of key fatty acid synthesis regulators FASN and ACACA, demonstrating that MBTPS2 acts through SREBP signaling to regulate lipogenesis and cholesterol metabolism in cancer cells.\",\n      \"method\": \"siRNA knockdown; RNA-Seq; qPCR pathway validation; Filipin III staining for cholesterol\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNA-Seq, qPCR, cholesterol staining) in direct KD experiment, single lab\",\n      \"pmids\": [\"36991255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A novel MBTPS2 missense variant (p.Val256Leu) causing BRESHECK syndrome impairs cell growth in cholesterol-depleted media, attenuates SREBP pathway activation, and fails to activate the ER stress response pathway, confirming that MBTPS2 function is required for both sterol-regulated transcription and ER stress signaling.\",\n      \"method\": \"In vitro modeling: cell growth in cholesterol-depleted media; SREBP reporter assay; ER stress response assay\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal functional assays in complementation system, single lab\",\n      \"pmids\": [\"34655156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBTPS2 overexpression exacerbates albuminuria and promotes ER stress and renal damage in a streptozotocin-induced type 1 diabetic nephropathy mouse model, while knockdown attenuates albuminuria; chemical chaperone reduction of ER stress rescues MBTPS2-exacerbated renal damage, linking MBTPS2 function to ER stress regulation in kidney.\",\n      \"method\": \"In vivo MBTPS2 overexpression and knockdown in STZ mouse model; albuminuria measurement; ER stress markers; 4-PBA rescue experiment\",\n      \"journal\": \"Archives of physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function in vivo with pharmacological rescue, single lab\",\n      \"pmids\": [\"32255378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lipogenesis signal cascade Scap-SREBP1-S1P/S2P orchestrates NF-κB homeostasis and spatiotemporal activation: Scap transports a Scap-SREBP1-IκBα supercomplex from the ER to the Golgi where MBTPS2 (S2P) cleaves SREBP1, liberating IκBα for IKK-mediated phosphorylation and NF-κB activation in response to LPS; inhibition of S2P diminishes LPS-induced NF-κB activation.\",\n      \"method\": \"Co-IP to identify Scap-SREBP1-IκBα complex; S2P inhibitor experiments; Scap/SREBP1 KO cells; LPS stimulation assays measuring NF-κB activation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus pharmacological inhibition plus genetic KO with defined molecular readout, single lab\",\n      \"pmids\": [\"37267109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBTPS2 is required for activating transcription factors involved in bone (OASIS) and cartilage development (BBF2H7), ER stress response (ATF6), and lipid metabolism (SREBP) via regulated intramembrane proteolysis; MBTPS2-OI patient fibroblasts show stronger downregulation of SREBP-dependent genes and altered fatty acid abundance compared to MBTPS2-IFAP/KFSD fibroblasts.\",\n      \"method\": \"RNA-sequencing transcriptome profiling of patient-derived fibroblasts; fatty acid quantification by GC-MS\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-Seq plus metabolomic profiling in patient-derived cells with comparison across disease alleles\",\n      \"pmids\": [\"34093655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous Mbtps2 knock-in (N455S) and knock-out mice show osteochondral abnormalities including thinned subchondral bone, altered osteocyte interconnectivity, and thickened articular cartilage with chondrocyte clustering; hemizygous loss-of-function leads to embryonic lethality in male mice, establishing an in vivo requirement for MBTPS2 in maintaining bone and cartilage homeostasis.\",\n      \"method\": \"Knock-in and knock-out mouse models; skeletal histomorphometry; microCT; confocal microscopy of lacunocanalicular network\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent mouse models with defined skeletal phenotypes and multiple imaging modalities\",\n      \"pmids\": [\"37797712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An intronic MBTPS2 variant (c.1437+4T>C) in horses causes partial skipping of exon 10, producing an aberrant MBTPS2 transcript and brindle coat phenotype, demonstrating that MBTPS2 function in skin requires correct splicing and that loss of MBTPS2 activity affects skin/hair follicle biology.\",\n      \"method\": \"Whole genome sequencing; RT-PCR transcript analysis; cosegregation analysis in a horse family\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular demonstration of splice defect with cosegregation in an animal model relevant to mammalian MBTPS2 function\",\n      \"pmids\": [\"27449517\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBTPS2 (site-2 protease, S2P) is a Golgi/ER membrane-embedded zinc metalloprotease with its active site (HEXXH motif and Asp467) positioned within the membrane bilayer, where it performs regulated intramembrane proteolysis of multiple substrate transcription factors—including SREBPs (regulating cholesterol and fatty acid homeostasis), ATF6 (mediating the ER unfolded protein response), OASIS, and BBF2H7—by cleaving their first transmembrane domain after a priming Site-1 protease cut, releasing active N-terminal fragments to the nucleus; it also participates in NF-κB spatial activation by cleaving SREBP1 at the Golgi to liberate IκBα, and loss-of-function mutations cause a spectrum of X-linked human diseases affecting skin, bone, and other tissues proportional to the degree of enzymatic impairment.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MBTPS2 (Site-2 Protease, S2P) is a polytopic membrane-embedded zinc metalloprotease that performs regulated intramembrane proteolysis of multiple transcription factor substrates—including SREBPs, ATF6, OASIS, and BBF2H7—thereby controlling cholesterol/fatty acid homeostasis, the ER unfolded protein response, and bone/cartilage development [PMID:9659902, PMID:11850408, PMID:34093655]. Its HEXXH zinc-binding motif and Asp467 residue are positioned within transmembrane segments, placing the catalytic center inside the lipid bilayer to cleave substrate transmembrane helices after priming by Site-1 protease [PMID:10419520]. MBTPS2 also participates in NF-κB spatial activation by cleaving SREBP1 at the Golgi within a Scap–SREBP1–IκBα supercomplex, liberating IκBα for IKK-mediated phosphorylation [PMID:37267109]. Loss-of-function mutations in MBTPS2 cause a spectrum of X-linked human disorders—including IFAP syndrome, KFSD, BRESHECK syndrome, and osteogenesis imperfecta—with clinical severity correlating to the degree of residual enzymatic activity [PMID:19361614, PMID:23316014, PMID:34655156].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"The identity of the protease responsible for Site-2 cleavage of SREBPs was unknown; complementation cloning of mutant CHO cells identified MBTPS2 as a membrane-bound zinc metalloprotease whose HEXXH motif is essential for liberating SREBP transcriptional domains, establishing S2P as a novel intramembrane protease.\",\n      \"evidence\": \"Complementation cloning in CHO cells deficient in Site-2 cleavage; HEXXH active-site mutagenesis\",\n      \"pmids\": [\"9659902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Exact topology and position of the active site within the membrane not yet resolved\",\n        \"Substrate range beyond SREBPs unknown\",\n        \"No structural data for S2P\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"How a metalloprotease active site could function within a hydrophobic membrane was unclear; topology mapping showed the HEIGH catalytic sequence and Asp467 reside within transmembrane segments with luminal hydrophilic loops, establishing that S2P catalyzes proteolysis inside the lipid bilayer.\",\n      \"evidence\": \"Protease protection assays, glycosylation site mapping in ER membranes, and Asp467 mutagenesis\",\n      \"pmids\": [\"10419520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of water access to the intramembrane active site unresolved\",\n        \"Structural basis for substrate entry into the active site unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Whether S2P cleaved substrates beyond SREBPs was unknown; demonstration that S2P is required for ATF6 processing during ER stress expanded S2P's role from lipid homeostasis to the unfolded protein response.\",\n      \"evidence\": \"S2P-deficient CHO cell complementation; UPR reporter assays; ATF6 cleavage and nuclear translocation assays\",\n      \"pmids\": [\"11850408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for dual substrate recognition (SREBP vs. ATF6) not determined\",\n        \"Other potential ER stress-related substrates not yet identified\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The molecular basis of IFAP syndrome was unknown; identification of MBTPS2 missense mutations that impair SREBP cleavage to varying degrees, with activity levels correlating to clinical severity, established MBTPS2 as the causative gene and linked enzymatic function to disease.\",\n      \"evidence\": \"Complementation of CHO M19 cells with five patient-derived MBTPS2 mutations; SRE-reporter and cholesterol-free growth assays\",\n      \"pmids\": [\"19361614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Pathogenic mechanisms in affected tissues (skin, hair follicles) not directly examined\",\n        \"Relative contribution of impaired SREBP vs. ATF6 processing to clinical features unclear\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether distinct MBTPS2 mutations cause allelic skin disorders was unclear; the p.Asn508Ser mutation was shown to reduce sterol responsiveness by approximately half, causing KFSD and extending the allelic disease spectrum.\",\n      \"evidence\": \"Functional expression in protease-deficient cells; sterol-responsive reporter assay\",\n      \"pmids\": [\"20672378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Asn508Ser affects ATF6 or other substrate processing not tested\",\n        \"Single lab finding\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The structural basis for genotype–phenotype correlations was unclear; systematic functional analysis of 11 patient variants showed that mutations clustering near the transmembrane active site cause greater enzymatic loss and more severe phenotypes, establishing a quantitative structure–function–disease relationship.\",\n      \"evidence\": \"Cell growth in lipid-free media and sterol-responsive transcription assays for 11 MBTPS2 variants from 13 families\",\n      \"pmids\": [\"23316014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of human S2P to map mutations precisely\",\n        \"Functional consequences for non-SREBP substrates not assessed\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Structural principles governing intramembrane proteolysis by S2P-family metalloproteases—including water access and substrate entry mechanisms—were partially elucidated through crystal and cryo-EM structures of family members.\",\n      \"evidence\": \"Review of crystal/cryo-EM structures with structure-guided biochemical analyses\",\n      \"pmids\": [\"26811996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"High-resolution structure of human MBTPS2 itself not available\",\n        \"Substrate-bound structure not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MBTPS2's role in bone and cartilage development was confirmed: patient fibroblasts with OI-causing mutations show stronger downregulation of SREBP targets and altered fatty acid profiles than IFAP/KFSD alleles, and MBTPS2 processes OASIS and BBF2H7 transcription factors involved in skeletal tissue formation.\",\n      \"evidence\": \"RNA-Seq transcriptome profiling and GC-MS fatty acid quantification in patient-derived fibroblasts across disease alleles\",\n      \"pmids\": [\"34093655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct cleavage of OASIS and BBF2H7 by MBTPS2 not demonstrated in this study with reconstituted assays\",\n        \"Mechanism linking altered fatty acid profiles to skeletal phenotype unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"BRESHECK syndrome was linked to MBTPS2: a novel p.Val256Leu variant impairs both SREBP pathway activation and ER stress response, confirming that severe loss of dual pathway activity underlies the most severe MBTPS2-associated phenotype.\",\n      \"evidence\": \"Cell growth in cholesterol-depleted media; SREBP reporter assay; ER stress response assay in complementation system\",\n      \"pmids\": [\"34655156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; whether this variant affects OASIS/BBF2H7 processing not tested\",\n        \"In vivo validation of BRESHECK mechanisms lacking\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MBTPS2 knockdown in prostate cancer cells confirmed that MBTPS2 acts through SREBP signaling to regulate cholesterol synthesis/uptake and fatty acid synthesis gene expression (FASN, ACACA), demonstrating functional relevance in cancer cell lipogenesis.\",\n      \"evidence\": \"siRNA knockdown in LNCaP cells; RNA-Seq; qPCR; Filipin III cholesterol staining\",\n      \"pmids\": [\"36991255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MBTPS2 is essential for tumor growth in vivo not tested\",\n        \"Contribution of ATF6 branch vs. SREBP branch in cancer context not dissected\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A previously unrecognized link between lipogenesis signaling and innate immunity was established: MBTPS2 cleaves SREBP1 at the Golgi within a Scap–SREBP1–IκBα supercomplex, liberating IκBα for IKK phosphorylation and NF-κB activation upon LPS stimulation.\",\n      \"evidence\": \"Co-IP identifying Scap–SREBP1–IκBα complex; S2P inhibitor and Scap/SREBP1 KO cells; LPS-stimulated NF-κB activation assays\",\n      \"pmids\": [\"37267109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal validation of the supercomplex by independent methods (e.g., size-exclusion chromatography) not reported\",\n        \"In vivo relevance for innate immune responses not demonstrated\",\n        \"Whether other S2P substrates contribute to NF-κB regulation unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo skeletal requirement for MBTPS2 was established: heterozygous Mbtps2 knock-in (N455S) and knockout mice exhibit osteochondral abnormalities, while hemizygous males show embryonic lethality, confirming essentiality for bone and cartilage homeostasis.\",\n      \"evidence\": \"Knock-in and knockout mouse models; skeletal histomorphometry; microCT; confocal imaging of lacunocanalicular network\",\n      \"pmids\": [\"37797712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular substrates responsible for skeletal phenotype in vivo not identified\",\n        \"Whether ER stress or SREBP pathway impairment is the primary driver of skeletal defects not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the high-resolution structure of human MBTPS2, the mechanism by which it selects among multiple substrates, the relative contributions of impaired SREBP vs. ATF6 vs. OASIS/BBF2H7 processing to each clinical phenotype, and whether MBTPS2-dependent NF-κB activation is physiologically relevant in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of human MBTPS2\",\n        \"Substrate selectivity mechanism unknown\",\n        \"Relative pathway contributions to distinct tissue phenotypes not dissected in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 12]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SREBF1\",\n      \"SREBF2\",\n      \"ATF6\",\n      \"MBTPS1\",\n      \"SCAP\",\n      \"NFKBIA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}