MBTPS1 encodes site-1 protease (S1P, also SKI-1 or PCSK8), a Ca2+-dependent subtilisin-like serine protease of the proprotein convertase family. It is a type I membrane protein with a lumenal peptidase S8 catalytic domain, made as a zymogen whose propeptide is removed autocatalytically in the ER. The mature enzyme acts mainly in the Golgi membrane, and a soluble form is also shed. Unlike the basic-residue-directed convertases, S1P cleaves after hydrophobic or small residues in R-X-hydrophobic-X motifs. It makes the first, lumenal cleavage in the regulated intramembrane proteolysis of membrane-bound transcription factors: SREBP-1 and SREBP-2 (after SCAP escorts them to the Golgi when sterols are low), ATF6 and ATF6B during the unfolded protein response, and the CREB3 family (LUMAN, OASIS/CREB3L1, BBF2H7/CREB3L2, CREB-H/CREB3L3). Site-2 protease (MBTPS2) then cuts within the membrane to release the transcriptionally active N-terminal domains. S1P also processes non-transcription-factor proproteins. Its cleavage of the GNPTAB alpha/beta precursor activates GlcNAc-1-phosphotransferase for mannose-6-phosphate tagging of lysosomal enzymes. It also processes FAM20C, the secretory-pathway kinase, as well as pro-BDNF and arenavirus glycoproteins. Through these substrates S1P controls lipid synthesis, the ER stress response, lysosome biogenesis, collagen export and skeletal development. Biallelic hypomorphic variants cause spondyloepiphyseal dysplasia Kondo-Fu type. A mitochondrial pool that stabilizes the ETFA/ETFB complex has also been reported, and variants are linked to CAOP syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | EXP PMID:34349020 Proteolytic processing of secretory pathway kinase Fam20C by... | ACCEPT | Summary: Golgi membrane localization of S1P, reported in the FAM20C processing study. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. The FAM20C study places S1P processing of FAM20C at the Golgi; the cached record is abstract-only, so the localization data are deferred to the curator. Supporting Evidence: file:human/MBTPS1/MBTPS1-uniprot.txt Cleaves the propeptide from FAM20C which is required for FAM20C secretion from the Golgi apparatus membrane and for enhancement of FAM20C kinase activity PMID:12782636 As the Site-1 protease is localized in the Golgi apparatus, both SREBP and ATF6 must relocate to the Golgi apparatus to be cleaved. |
| GO:0000139 Golgi membrane | EXP PMID:9990022 Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed... | ACCEPT | Summary: Golgi localization of SKI-1 by immunocytochemistry in transfected HK293 cells. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: PMID:9990022 Immunocytochemical analysis of stably transfected HK293 cells shows that SKI-1 is present in the Golgi apparatus and within small punctate structures reminiscent of endosomes. |
| GO:0000139 Golgi membrane | IDA PMID:9990022 Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed... | ACCEPT | Summary: Golgi localization of SKI-1 by immunocytochemistry in transfected HK293 cells. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: PMID:9990022 Immunocytochemical analysis of stably transfected HK293 cells shows that SKI-1 is present in the Golgi apparatus and within small punctate structures reminiscent of endosomes. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (Golgi apparatus membrane). Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: PMID:9990022 Immunocytochemical analysis of stably transfected HK293 cells shows that SKI-1 is present in the Golgi apparatus and within small punctate structures reminiscent of endosomes. PMID:12782636 As the Site-1 protease is localized in the Golgi apparatus, both SREBP and ATF6 must relocate to the Golgi apparatus to be cleaved. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1655842 | ACCEPT | Summary: Reactome: S1P cleaves SREBP1A/1C/2 in the Golgi membrane. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: Reactome:R-HSA-1655842 S1P (MBTPS1, SKI-1), a membrane-bound protease in the Golgi, cleaves the intralumenal loop of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2, which remains bound to the membrane. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-381135 | ACCEPT | Summary: Reactome: S1P cleaves ATF6-alpha in the Golgi. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: Reactome:R-HSA-381135 Once in the Golgi, ATF6-alpha undergoes two sequential proteolytic cleavages. S1P catalyzes the first of these |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-8874145 | ACCEPT | Summary: Reactome: S1P cleaves ATF6B at the Golgi membrane. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: Reactome:R-HSA-8874145 ATF6B is anchored in the Golgi membrane and cleaved in the lumenal domain to release a N-terminal fragment into the cytosol |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-8874204 | ACCEPT | Summary: Reactome: S1P cleaves CREB3 (LUMAN) at the Golgi membrane. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: Reactome:R-HSA-8874204 In the Golgi membrane, CREB3 (LUMAN) is cleaved by regulated intramembrane proteolysis |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-8874206 | ACCEPT | Summary: Reactome: S1P cleaves CREB3L3 at the Golgi membrane. Reason: MBTPS1 is a type I membrane protein whose mature form resides in the Golgi membrane, the compartment to which SREBP (via SCAP), ATF6 and CREB3-family substrates are transported for cleavage. Golgi membrane is the core site of its activity. Supporting Evidence: Reactome:R-HSA-8874206 CREB3L3 at the Golgi membrane is cleaved in the luminal domain (LLarena et al. 2010) by MBTPS1 (S1P) |
| GO:0004175 endopeptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of endopeptidase activity from mouse Mbtps1. Reason: Correct but less specific than the evidence supports: S1P is a subtilisin-like (peptidase S8) Ca2+-dependent serine endopeptidase. Refine to serine-type endopeptidase activity, which the gene already carries by IDA/IMP/EXP/IBA. Proposed replacements: serine-type endopeptidase activity Supporting Evidence: PMID:9990022 In vitro studies suggest that SKI-1 is a Ca2+-dependent serine proteinase exhibiting a wide pH optimum for cleavage of pro-brain-derived neurotrophic factor. file:human/MBTPS1/MBTPS1-uniprot.txt Belongs to the peptidase S8 family. |
| GO:0004252 serine-type endopeptidase activity | EXP PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | ACCEPT | Summary: S1P is required for the first (RxxL-dependent) cleavage of ATF6 in CHO mutant cells. Reason: Core catalytic activity. S1P-deficient cells are defective in ATF6 processing, which requires the RxxL S1P recognition motif. Supporting Evidence: PMID:11163209 Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. PMID:11163209 ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. |
| GO:0004252 serine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (PTN002465698, peptidase S8 subtilisin clade) for serine-type endopeptidase activity. Reason: MBTPS1 retains the S8 catalytic triad and has direct experimental evidence for this activity; the target appearing among the IBA sources reflects its own experimental grounding. The node placement within the catalytically active subtilisin clade is sound. Supporting Evidence: file:human/MBTPS1/MBTPS1-uniprot.txt Belongs to the peptidase S8 family. PMID:10644685 We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2. |
| GO:0004252 serine-type endopeptidase activity | IDA PMID:34349020 Proteolytic processing of secretory pathway kinase Fam20C by... | ACCEPT | Summary: S1P cleaves the FAM20C propeptide. Reason: Direct evidence for S1P serine endopeptidase activity on FAM20C (abstract-only cache; deferred to the curator for assay details). Supporting Evidence: PMID:34349020 The secretion and kinase activity of Fam20C are governed by site-1 protease (S1P), a key regulator of cholesterol homeostasis. PMID:34349020 We find that only mature Fam20C processed by S1P functions in osteoblast differentiation and mineralization. |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (InterPro IPR036852 peptidase S8/S53 domain superfamily, mouse ortholog). Reason: Consistent with the experimentally established core activity. Supporting Evidence: file:human/MBTPS1/MBTPS1-uniprot.txt Belongs to the peptidase S8 family. PMID:9990022 In vitro studies suggest that SKI-1 is a Ca2+-dependent serine proteinase exhibiting a wide pH optimum for cleavage of pro-brain-derived neurotrophic factor. |
| GO:0004252 serine-type endopeptidase activity | IMP PMID:21719679 A key enzyme in the biogenesis of lysosomes is a protease th... | ACCEPT | Summary: S1P cleaves the GNPTAB alpha/beta subunit precursor; S1P-deficient cells fail to activate it. Reason: Core catalytic activity applied to a non-transcription-factor substrate. Supporting Evidence: PMID:21719679 Here we found that the Ξ±/Ξ²-subunit precursor is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. PMID:21719679 S1P-deficient cells failed to activate the Ξ±/Ξ²-subunit precursor and exhibited a mucolipidosis II-like phenotype. |
| GO:0004252 serine-type endopeptidase activity | TAS PMID:9809072 Molecular identification of the sterol-regulated luminal pro... | ACCEPT | Summary: Cloning of S1P as the subtilisin-like protease that cleaves SREBPs in the luminal loop. Reason: Core catalytic activity. Supporting Evidence: PMID:9809072 Release is initiated by Site-1 protease (S1P), which cleaves SREBPs in the ER luminal loop between two membrane-spanning regions. PMID:9809072 The cDNA encodes S1P, an intraluminal 1052-amino-acid membrane-bound subtilisin-like protease. |
| GO:0005515 protein binding | IPI PMID:34349020 Proteolytic processing of secretory pathway kinase Fam20C by... | REMOVE | Summary: Interaction of S1P with its substrate FAM20C (Q8IXL6). Reason: Bare protein binding is uninformative. The interaction reflects enzyme-substrate engagement that is already captured by serine-type endopeptidase activity and protein processing; removal does not dispute the interaction. Supporting Evidence: PMID:34349020 The secretion and kinase activity of Fam20C are governed by site-1 protease (S1P), a key regulator of cholesterol homeostasis. |
| GO:0005515 protein binding | IPI PMID:35362222 S1P defects cause a new entity of cataract, alopecia, oral m... | REMOVE | Summary: Co-IP/MS interaction of S1P with ETFA (P13804) and ETFB (P38117). Reason: Bare protein binding is uninformative. The reported S1P-ETFA/ETFB complex is a single-study finding (said to be independent of S1P protease activity, stabilising ETF and promoting its flavination); no specific, well-defined MF term is supported, so the generic row is removed without disputing the interaction. Supporting Evidence: PMID:35362222 we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. PMID:35362222 S1P enhances ETFA/ETFB flavination and maintains its stability. |
| GO:0005576 extracellular region | EXP PMID:9990022 Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed... | KEEP AS NON CORE | Summary: A 98 kDa form of SKI-1 is shed into the medium. Reason: Shedding of a soluble form is documented, but the physiological substrates are cleaved by the membrane-bound Golgi enzyme; extracellular location is peripheral. Supporting Evidence: PMID:9990022 Late along the secretory pathway some of the membrane-bound enzyme is shed into the medium as a 98-kDa form. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping (Secreted). Reason: As for the EXP row: a shed 98 kDa form exists but is not the main functional pool. Supporting Evidence: PMID:9990022 Late along the secretory pathway some of the membrane-bound enzyme is shed into the medium as a 98-kDa form. |
| GO:0005739 mitochondrion | IDA PMID:35362222 S1P defects cause a new entity of cataract, alopecia, oral m... | KEEP AS NON CORE | Summary: S1P colocalizes with mitochondrial markers in the CAOP syndrome study. Reason: A single 2022 study reports a mitochondrial pool of S1P that associates with ETFA/ETFB. The data are taken at face value but the topology (S1P has an ER signal peptide and lumenal catalytic domain) is unexplained, so the location is non-core pending independent confirmation. ORGANELLES check (2026-11-03): the full text was read. The fractionation is better controlled than a crude pellet, since the mitochondrial fraction (COX IV) was separated from an ER fraction (ERp72), Golgi (GM130) and lysosomes (LAMP1), so the ER/MAM carry-over concern does not by itself explain the signal; the row stays KEEP_AS_NON_CORE as direct evidence under rule 2. Stays at the root: the same paper's proteinase K assay found S1P protected after removal of the outer membrane and read this as matrix, and its partners ETFA/ETFB are matrix flavoproteins, but these lines conflict with S1P's curated ER and Golgi single-pass type I membrane topology with a lumenal protease domain, the protection assay only shows a location inside the outer membrane (inner membrane or matrix), and all of it comes from one study, so no GO:0005759 row is added. Supporting Evidence: PMID:35362222 confocal immunofluorescence indicated that S1P colocalized with the mitochondrial tracer PMID:35362222 we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. PMID:35362222 Biochemical fractionation of the wholeβcell lysate (WCL), cytosol (Cyto, tubulin), mitochondria (Mito, COX IV), lysosomes (Lyso, LAMP1), Golgi apparatus (Golgi, GM130), endoplasmic reticulum (ER, ERp72) PMID:35362222 S1P could still be detected after elimination of the mitochondrial outer membrane, which indicated that S1P resides in the mitochondrial matrix space |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping (Mitochondrion), derived from PMID:35362222. Reason: Same single-study basis as the IDA row; kept as non-core. ORGANELLES check (2026-11-03): UniProt's Mitochondrion location (SL-0173) is curated from PMID:35362222 (ECO:0000269), so the keyword mapping is sound and consistent with the IDA row; it stays at the root for the reasons given there (matrix reading from one protease-protection assay conflicts with the ER/Golgi type I membrane topology). Supporting Evidence: PMID:35362222 confocal immunofluorescence indicated that S1P colocalized with the mitochondrial tracer PMID:35362222 S1P could still be detected after elimination of the mitochondrial outer membrane, which indicated that S1P resides in the mitochondrial matrix space file:human/MBTPS1/MBTPS1-uniprot.txt Secreted {ECO:0000269|PubMed:9990022}. Mitochondrion {ECO:0000269|PubMed:35362222}. Note=May sort to other organelles |
| GO:0005788 endoplasmic reticulum lumen | TAS PMID:9809072 Molecular identification of the sterol-regulated luminal pro... | MODIFY | Summary: S1P described as an intraluminal membrane-bound protease. Reason: MBTPS1 is a single-pass type I membrane protein whose catalytic domain faces the lumen; it is not a soluble ER-lumen protein. The intended meaning (luminal-facing ER-resident form) is captured by ER membrane, which the gene already carries by EXP. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:9809072 The cDNA encodes S1P, an intraluminal 1052-amino-acid membrane-bound subtilisin-like protease. PMID:9990022 In the endoplasmic reticulum of either LoVo or HK293 cells, proSKI-1 is processed into two membrane-bound forms of SKI-1 (120 and 106 kDa) differing by the nature of their N-glycosylation. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | MODIFY | Summary: Reactome places MBTPS1 among FAM20C substrates phosphorylated in the secretory-pathway lumen. Reason: The Reactome event concerns FAM20C phosphorylation of secretory-pathway proteins, in which the lumenal domain of MBTPS1 is a substrate; the protein itself is membrane-anchored. ER membrane (already supported by EXP) is the appropriate location. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:9990022 In the endoplasmic reticulum of either LoVo or HK293 cells, proSKI-1 is processed into two membrane-bound forms of SKI-1 (120 and 106 kDa) differing by the nature of their N-glycosylation. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:9990022 Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed... | KEEP AS NON CORE | Summary: ProSKI-1 is processed in the ER into membrane-bound forms. Reason: ER membrane is a genuine location (zymogen maturation by propeptide autoprocessing) but substrate cleavage occurs mainly in the Golgi. Supporting Evidence: PMID:9990022 In the endoplasmic reticulum of either LoVo or HK293 cells, proSKI-1 is processed into two membrane-bound forms of SKI-1 (120 and 106 kDa) differing by the nature of their N-glycosylation. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping (Endoplasmic reticulum membrane). Reason: As for the EXP row. Supporting Evidence: PMID:9990022 In the endoplasmic reticulum of either LoVo or HK293 cells, proSKI-1 is processed into two membrane-bound forms of SKI-1 (120 and 106 kDa) differing by the nature of their N-glycosylation. |
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA (PTN002465706, S1P orthologs incl. Arabidopsis SBT6.1) for Golgi apparatus. Reason: The S1P clade localization to the Golgi is well-founded, but the protein is a type I membrane protein and the more specific Golgi membrane is supported by multiple experimental rows for this gene. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002465706 SUPPORTS TRANSFER S1P-orthologue node; Golgi residence is inherited across plant and animal S1P. The MODIFY only sharpens the term to Golgi membrane, which the human protein's experimental rows support. UniProtKB:Q14703 SUPPORTS TRANSFER The target's own experimental Golgi localization is among the descendant evidence for the node; expected, not circular. Proposed replacements: Golgi membrane Supporting Evidence: PMID:9990022 Immunocytochemical analysis of stably transfected HK293 cells shows that SKI-1 is present in the Golgi apparatus and within small punctate structures reminiscent of endosomes. PMID:30046013 Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. |
| GO:0005795 Golgi stack | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of Golgi stack from mouse Mbtps1. Reason: Compatible with the Golgi residence of S1P (cis/medial Golgi cleavage of SREBP/ATF6), but sub-Golgi localization has not been characterized in detail for the human protein; Golgi membrane is the core location. Supporting Evidence: PMID:9990022 Immunocytochemical analysis of stably transfected HK293 cells shows that SKI-1 is present in the Golgi apparatus and within small punctate structures reminiscent of endosomes. |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA for proteolysis (InterPro peptidase S8). Reason: True but generic. S1P's proteolysis is the first cleavage of regulated intramembrane proteolysis of membrane-bound transcription factors and limited processing of other proproteins (GNPTAB, FAM20C, pro-BDNF); both specific descendants are supported and already carried by the gene. Proposed replacements: membrane protein intracellular domain proteolysis protein processing Supporting Evidence: PMID:9809072 Release is initiated by Site-1 protease (S1P), which cleaves SREBPs in the ER luminal loop between two membrane-spanning regions. PMID:21719679 Here we found that the Ξ±/Ξ²-subunit precursor is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. |
| GO:0006508 proteolysis | IMP PMID:21719679 A key enzyme in the biogenesis of lysosomes is a protease th... | MODIFY | Summary: S1P-dependent cleavage of the GNPTAB alpha/beta precursor. Reason: True but generic; the cleavage is a protein processing (maturation) event. Refined to protein processing; RIP is listed for consistency with the other proteolysis rows. Proposed replacements: membrane protein intracellular domain proteolysis protein processing Supporting Evidence: PMID:21719679 Here we found that the Ξ±/Ξ²-subunit precursor is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. PMID:21719679 S1P-deficient cells failed to activate the Ξ±/Ξ²-subunit precursor and exhibited a mucolipidosis II-like phenotype. |
| GO:0006508 proteolysis | TAS PMID:9809072 Molecular identification of the sterol-regulated luminal pro... | MODIFY | Summary: S1P cleaves SREBPs in the luminal loop. Reason: True but generic; refined to membrane protein intracellular domain proteolysis (RIP of SREBP) and protein processing. Proposed replacements: membrane protein intracellular domain proteolysis protein processing Supporting Evidence: PMID:9809072 Release is initiated by Site-1 protease (S1P), which cleaves SREBPs in the ER luminal loop between two membrane-spanning regions. |
| GO:0007040 lysosome organization | IMP PMID:21719679 A key enzyme in the biogenesis of lysosomes is a protease th... | KEEP AS NON CORE | Summary: S1P-deficient cells show a mucolipidosis II-like phenotype due to failure to activate GlcNAc-1-phosphotransferase. Reason: S1P contributes to lysosome biogenesis through a specific catalytic step (GNPTAB precursor cleavage needed for M6P tagging of lysosomal hydrolases). The organelle-level term is acceptable as a non-core, downstream consequence. Supporting Evidence: PMID:21719679 S1P-deficient cells failed to activate the Ξ±/Ξ²-subunit precursor and exhibited a mucolipidosis II-like phenotype. PMID:21719679 Thus, S1P functions in the biogenesis of lysosomes PMID:30046013 S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes. |
| GO:0007095 mitotic G2 DNA damage checkpoint signaling | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of mitotic G2 DNA damage checkpoint signaling from mouse Mbtps1. Reason: S1P performs the first cleavage of CREB3L1 after DNA damage/ER stress, and released CREB3L1 then restrains cell-cycle progression. S1P does not itself participate in checkpoint signaling; the term describes a downstream effect of a substrate transcription factor. Supporting Evidence: file:human/MBTPS1/MBTPS1-uniprot.txt 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 |
| GO:0008236 serine-type peptidase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IPR000209 peptidase S8/S53 domain) for serine-type peptidase activity. Reason: Correct but general; S1P is an endopeptidase that cleaves internal bonds of its substrates. Refine to serine-type endopeptidase activity, already carried by the gene. Proposed replacements: serine-type endopeptidase activity Supporting Evidence: file:human/MBTPS1/MBTPS1-uniprot.txt Belongs to the peptidase S8 family. PMID:10644685 We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2. |
| GO:0016485 protein processing | IDA PMID:34349020 Proteolytic processing of secretory pathway kinase Fam20C by... | ACCEPT | Summary: S1P removes the FAM20C propeptide, producing the mature secreted, active kinase. Reason: Protein processing of non-transcription-factor substrates (FAM20C, GNPTAB, pro-BDNF) is a core aspect of S1P function as a proprotein convertase. Supporting Evidence: PMID:34349020 We find that only mature Fam20C processed by S1P functions in osteoblast differentiation and mineralization. file:human/MBTPS1/MBTPS1-uniprot.txt Cleaves the propeptide from FAM20C which is required for FAM20C secretion from the Golgi apparatus membrane and for enhancement of FAM20C kinase activity |
| GO:0030968 endoplasmic reticulum unfolded protein response | TAS Reactome:R-HSA-381119 | ACCEPT | Summary: Reactome UPR pathway: S1P cleaves ATF6, ATF6B and CREB3-family transducers. Reason: S1P catalyses an obligatory step in activating several ER stress transducers (ATF6, ATF6B, CREB3, CREB3L1-3), not only ATF6; the general ER UPR term is appropriate alongside the ATF6-specific term. Supporting Evidence: Reactome:R-HSA-381119 mobilization of ATF6, ATF6B, CREB3 factors and IRE1 leads to increased transcription of genes encoding chaperones PMID:16417584 Here, we showed that OASIS is processed by Site-1 and -2 proteases (S1P and S2P), enzymes that reside at the Golgi apparatus and process activating transcription factor 6 (ATF6), in response to ER stress. PMID:30046013 The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. |
| GO:0030968 endoplasmic reticulum unfolded protein response | TAS Reactome:R-HSA-8874177 | ACCEPT | Summary: Reactome: S1P and S2P cleave ATF6B during ER stress. Reason: As above; S1P performs the first cleavage of ATF6B. Supporting Evidence: Reactome:R-HSA-8874177 The Golgi-resident proteases MBTPS1 (S1P) and MBTPS2 (S2P) cleave ATF6B and release the cytoplasmic (N-terminal) domain |
| GO:0031293 membrane protein intracellular domain proteolysis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of membrane protein intracellular domain proteolysis from mouse. Reason: S1P catalyses the first, luminal cleavage of regulated intramembrane proteolysis that ultimately releases the cytosolic domains of SREBPs, ATF6 and CREB3-family factors; it does part of the work of this process. Supporting Evidence: PMID:8674110 The first, regulated by sterols, occurs in the lumenal loop. PMID:9809072 Release is initiated by Site-1 protease (S1P), which cleaves SREBPs in the ER luminal loop between two membrane-spanning regions. PMID:11163209 Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. |
| GO:0031293 membrane protein intracellular domain proteolysis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from hamster S1P (Q9Z2A8). Reason: As above; the hamster CHO-cell genetics established the S1P step in SREBP release. Supporting Evidence: PMID:9809072 Release is initiated by Site-1 protease (S1P), which cleaves SREBPs in the ER luminal loop between two membrane-spanning regions. PMID:8674110 The first, regulated by sterols, occurs in the lumenal loop. |
| GO:0034976 response to endoplasmic reticulum stress | ISS GO_REF:0000024 | MODIFY | Summary: ISS from hamster S1P (Q9Z2A8) for response to ER stress. Reason: True but general. The participation of S1P in ER stress responses is through cleavage of ATF6/ATF6B (and CREB3 family) and is better captured by ATF6-mediated unfolded protein response, which the gene already carries. Proposed replacements: ATF6-mediated unfolded protein response Supporting Evidence: PMID:11163209 Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. PMID:11163209 We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis. |
| GO:0036500 ATF6-mediated unfolded protein response | TAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | ACCEPT | Summary: Review: ATF6 is cleaved by S1P and S2P in the Golgi during the UPR. Reason: S1P catalyses the first cleavage step of ATF6 activation; core process. Supporting Evidence: PMID:22934019 ATF6 activation as part of the UPR leads to its translocation to the Golgi and cleavage by site-1 protease (S1P) and S2P. PMID:11163209 Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. |
| GO:0036500 ATF6-mediated unfolded protein response | TAS Reactome:R-HSA-381033 | ACCEPT | Summary: Reactome: ATF6-alpha is cleaved by S1P and S2P in the Golgi to activate chaperone genes. Reason: Core process, as above. Supporting Evidence: Reactome:R-HSA-381033 Upon interaction of BiP with unfolded proteins in the ER, ATF6-alpha dissociates and transits to the Golgi where it is cleaved by the S1P and S2P proteases that reside in the Golgi PMID:12782636 AEBSF also inhibited production of the mature form of SREBP-2 that was induced in response to sterol depletion, and appeared to directly prevent cleavage of ATF6alpha and ATF6beta by inhibiting Site-1 protease. |
| GO:0045540 regulation of cholesterol biosynthetic process | TAS Reactome:R-HSA-1655829 | MODIFY | Summary: Reactome: SREBP cleavage by S1P then S2P regulates cholesterol biosynthesis. Reason: S1P cleavage is the activating step for SREBPs, so the effect is positive. Refine to positive regulation of cholesterol biosynthetic process, the term used for the S1P/S2P proteases in mouse and for human MBTPS2. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: Reactome:R-HSA-1655829 In the Golgi SREBP is cleaved by S1P and then by S2P, releasing the N-terminal fragment of SREBP into the cytosol. PMID:9809072 We propose that S1P is the sterol-regulated protease that controls lipid metabolism in animal cells. |
| GO:0051604 protein maturation | IDA PMID:21719679 A key enzyme in the biogenesis of lysosomes is a protease th... | MODIFY | Summary: S1P cleavage of the GNPTAB alpha/beta precursor is required for GlcNAc-1-phosphotransferase activity. Reason: Correct but general: the maturation is achieved by peptide-bond cleavage, i.e. protein processing (a descendant of protein maturation already carried by the gene). Proposed replacements: protein processing Supporting Evidence: PMID:21719679 Here we found that the Ξ±/Ξ²-subunit precursor is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. PMID:21719679 S1P-deficient cells failed to activate the Ξ±/Ξ²-subunit precursor and exhibited a mucolipidosis II-like phenotype. |
| GO:0051604 protein maturation | IMP PMID:21719679 A key enzyme in the biogenesis of lysosomes is a protease th... | MODIFY | Summary: S1P-deficient cells fail to activate the GNPTAB alpha/beta precursor. Reason: As for the IDA row; refine to protein processing. Proposed replacements: protein processing Supporting Evidence: PMID:21719679 S1P-deficient cells failed to activate the Ξ±/Ξ²-subunit precursor and exhibited a mucolipidosis II-like phenotype. |
| GO:0060627 regulation of vesicle-mediated transport | IMP PMID:30046013 Site-1 protease deficiency causes human skeletal dysplasia d... | KEEP AS NON CORE | Summary: S1P deficiency impairs BBF2H7 activation, TANGO1/SEC23A expression and mega-vesicle collagen export, and M6P-dependent lysosomal enzyme delivery. Reason: S1P influences vesicle trafficking indirectly, by activating BBF2H7/CREB3L2 (which induces the mega-vesicle machinery) and GNPTAB (M6P sorting). This is a legitimate regulatory role but downstream of the core protease activity. Supporting Evidence: PMID:30046013 The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. PMID:30046013 S1P proteolytically activates membrane-bound transcription factor BBF2H7, a key UPR transducer, to regulate expression of a set of genes ( Sec23a, Tango1, Sedlin, and Hsp47 ) essential for the formation of mega vesicles in ECM-secreting cells PMID:30046013 S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes. |
| GO:0016540 protein autoprocessing | IDA PMID:10644685 Biosynthesis and enzymatic characterization of human SKI-1/S... | NEW | Summary: S1P is synthesized as a zymogen whose propeptide (18-186) is removed by intramolecular autocatalytic cleavage after RRLL186, followed by further cleavage of prosegment fragments. Reason: Autoprocessing passes the participation test because the substrate is the enzyme itself. Peptides spanning the RRLL186 and RSLK137 prosegment sites are cleaved by SKI-1, and genomic analysis describes self-activation by intramolecular cleavage. UniProt records the autolytic cleavage site with experimental evidence. Supporting Evidence: PMID:10644685 Among the candidate peptides encompassing sections of the SKI-1 prosegment, the RSLK(137)- and RRLL(186)-containing peptides were best cleaved by this enzyme. PMID:10944850 exons 2 and 3 encode the pro-peptide sequence that is released when S1P is self-activated by intramolecular cleavage file:human/MBTPS1/MBTPS1-uniprot.txt The propeptide is autocatalytically removed through an intramolecular cleavage after Leu-186. |
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Download this section (compressed HTML)Q: Should the S1P/S2P proteases carry GO:0032933 SREBP signaling pathway? In human, mouse and rat it is held by SCAP, INSIG1/2, SREBF1/2 and ERLIN1/2 but by no protease, while the parallel ATF6 pathway term (GO:0036500) is annotated to S1P and S2P.
Q: How does a mitochondrial pool of S1P arise given its ER signal peptide and lumenal catalytic domain, and is the reported protease-independent stabilization of ETFA/ETFB reproducible in other cell types?
Q: What determines substrate selection in SEDKF patients with about 1% residual S1P, where SREBP processing is preserved but BBF2H7 and GNPTAB processing fail?
Experiment: Titrate S1P activity (inducible knockdown or graded inhibitor PF-429242) in chondrocytes and fibroblasts and quantify processing of SREBP2, ATF6, CREB3L2 and GNPTAB in parallel to define substrate-specific sensitivity thresholds.
Experiment: Use protease-protection and organelle fractionation with epitope-tagged endogenous MBTPS1 to test for, and map the topology of, the proposed mitochondrial S1P pool and its association with ETFA/ETFB.
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