MBTPS2 encodes site-2 protease (S2P), an intramembrane zinc metalloprotease of the M50 family. It is a polytopic membrane protein in the Golgi with cytosolic N- and C-termini, an HEIGH zinc-binding motif, and an Asp ligand buried within membrane-spanning segments. S2P acts after site-1 protease (MBTPS1) in regulated intramembrane proteolysis. Once S1P has trimmed the lumenal domain of a membrane-bound transcription factor, S2P cleaves within its transmembrane helix, which depends on a helix-destabilizing Asn-Pro motif in the substrate. This releases the cytosolic N-terminal bZIP domain, which enters the nucleus. Its principal substrates are SREBP-1 and SREBP-2, which drive cholesterol and fatty acid synthesis and uptake, and ATF6/ATF6B, which induce ER chaperones in the unfolded protein response. S2P also cleaves the CREB3-family factors OASIS (CREB3L1), BBF2H7 (CREB3L2) and CREB-H (CREB3L3). S2P is essential for cholesterol prototrophy and the ATF6 branch of the ER stress response. X-linked hypomorphic variants cause IFAP syndrome, keratosis follicularis spinulosa decalvans, X-linked Olmsted syndrome and osteogenesis imperfecta type XIX. In the bone disease, defective processing of OASIS, ATF6 and SREBP impairs collagen secretion and osteoblast differentiation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (Golgi apparatus membrane). Reason: S2P is a polytopic Golgi membrane protein; the S1P-trimmed SREBP, ATF6 and CREB3-family intermediates are cleaved by S2P in the Golgi membrane. Core location. Supporting Evidence: 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. Reactome:R-HSA-1655851 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol. |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS with MBTPS1 (Q14703) as the cited source; asserts Golgi membrane as the site of activity. Reason: S2P is a polytopic Golgi membrane protein; the S1P-trimmed SREBP, ATF6 and CREB3-family intermediates are cleaved by S2P in the Golgi membrane. Core location. The cited WITH entity is the partner protease S1P rather than an S2P ortholog, but the conclusion is independently supported for S2P. Supporting Evidence: 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. 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 |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1655851 | ACCEPT | Summary: Reactome: S2P cleaves SREBP1A/1C/2 in the Golgi membrane. Reason: S2P is a polytopic Golgi membrane protein; the S1P-trimmed SREBP, ATF6 and CREB3-family intermediates are cleaved by S2P in the Golgi membrane. Core location. Supporting Evidence: Reactome:R-HSA-1655851 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-420818 | ACCEPT | Summary: Reactome: S2P performs the second ATF6-alpha cleavage in the Golgi. Reason: S2P is a polytopic Golgi membrane protein; the S1P-trimmed SREBP, ATF6 and CREB3-family intermediates are cleaved by S2P in the Golgi membrane. Core location. Supporting Evidence: Reactome:R-HSA-420818 S2P catalyzes the second of these, cleaving the ATF6-alpha S1P cleavage product within its transmembrane domain. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-8874122 | ACCEPT | Summary: Reactome: S2P cleaves ATF6B at the Golgi membrane. Reason: S2P is a polytopic Golgi membrane protein; the S1P-trimmed SREBP, ATF6 and CREB3-family intermediates are cleaved by S2P in the Golgi membrane. Core location. Supporting Evidence: Reactome:R-HSA-8874122 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-8874201 | ACCEPT | Summary: Reactome: S2P cleaves CREB3L3 at the Golgi membrane. Reason: S2P is a polytopic Golgi membrane protein; the S1P-trimmed SREBP, ATF6 and CREB3-family intermediates are cleaved by S2P in the Golgi membrane. Core location. Supporting Evidence: Reactome:R-HSA-8874201 After cleavage by MBTPS1, CREB3L3 in the Golgi membrane is cleaved by MBTPS2 (S2P) near the cytoplasmic face of the transmembrane domain |
| GO:0004222 metalloendopeptidase activity | EXP PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | ACCEPT | Summary: S2P is required for the second, intramembrane cleavage of ATF6, which depends on the asparagine/proline motif. Reason: Core activity: zinc metalloendopeptidase cleaving substrates within transmembrane segments. 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 was blocked completely in cells lacking S2P and partially in cells lacking S1P. |
| GO:0004222 metalloendopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (PTN004417004, S2P clade with Arabidopsis S2P) for metalloendopeptidase activity. Reason: Human S2P has its own experimental evidence for this activity (and appears among the IBA sources as expected). The M50 HEXXH catalytic motif is conserved, so node placement is sound. Supporting Evidence: file:human/MBTPS2/MBTPS2-uniprot.txt Belongs to the peptidase M50A family. PMID:9659902 S2P defines a new family of polytopic membrane proteins that contain an HEXXH sequence characteristic of zinc metalloproteases. |
| GO:0004222 metalloendopeptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IPR001193 MBTPS2) for metalloendopeptidase activity. Reason: Consistent with the experimentally established core activity. Supporting Evidence: file:human/MBTPS2/MBTPS2-uniprot.txt Belongs to the peptidase M50A family. PMID:9659902 Mutation of the putative zinc-binding residues abolishes S2P activity. |
| GO:0004222 metalloendopeptidase activity | TAS PMID:9659902 Complementation cloning of S2P, a gene encoding a putative m... | ACCEPT | Summary: Cloning of S2P as a putative HEXXH zinc metalloprotease required for Site-2 cleavage of SREBPs. Reason: Core activity; the zinc-binding residues are required for function. Supporting Evidence: PMID:9659902 S2P defines a new family of polytopic membrane proteins that contain an HEXXH sequence characteristic of zinc metalloproteases. PMID:9659902 Mutation of the putative zinc-binding residues abolishes S2P activity. PMID:9659902 S2P encodes an unusual metalloprotease that cleaves proteins within transmembrane segments. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA (PTN004417004) for cytoplasm. Reason: Technically true (the Golgi membrane is part of the cytoplasm), but S2P is an integral polytopic membrane protein with its active site within the bilayer; it is not a soluble cytoplasmic protein. Refine to Golgi membrane, already carried by the gene. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN004417004 SUPPORTS TRANSFER S2P-clade node; the location propagated is true at the level asserted but less precise than the integral Golgi-membrane location supported for human S2P. UniProtKB:O43462 SUPPORTS TRANSFER The target's own IDA cytoplasm row is among the descendant evidence; expected, not circular. Proposed replacements: Golgi membrane Supporting Evidence: PMID:10419520 Both the NH(2) and COOH termini of S2P face the cytosol. Reactome:R-HSA-1655851 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol. |
| GO:0005737 cytoplasm | IDA PMID:19361614 IFAP syndrome is caused by deficiency in MBTPS2, an intramem... | MODIFY | Summary: Cytoplasmic (non-nuclear) immunostaining of MBTPS2 in the IFAP syndrome study. Reason: Technically true (the Golgi membrane is part of the cytoplasm), but S2P is an integral polytopic membrane protein with its active site within the bilayer; it is not a soluble cytoplasmic protein. Refine to Golgi membrane, already carried by the gene. The cached record is abstract-only; the curated UniProt location derives from this paper. Proposed replacements: Golgi membrane Supporting Evidence: file:human/MBTPS2/MBTPS2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:19361614} PMID:10419520 Both the NH(2) and COOH termini of S2P face the cytosol. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: UniProt subcellular location mapping (Cytoplasm). Reason: Technically true (the Golgi membrane is part of the cytoplasm), but S2P is an integral polytopic membrane protein with its active site within the bilayer; it is not a soluble cytoplasmic protein. Refine to Golgi membrane, already carried by the gene. Proposed replacements: Golgi membrane Supporting Evidence: file:human/MBTPS2/MBTPS2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:19361614} PMID:10419520 Both the NH(2) and COOH termini of S2P face the cytosol. |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IPR001193, IPR008915 peptidase M50) for proteolysis. Reason: True but generic. S2P's proteolysis is intramembrane cleavage that releases the cytosolic domains of membrane-bound transcription factors, i.e. membrane protein intracellular domain proteolysis (already carried by the gene). Proposed replacements: membrane protein intracellular domain proteolysis Supporting Evidence: PMID:9659902 S2P encodes an unusual metalloprotease that cleaves proteins within transmembrane segments. PMID:10805775 Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. |
| GO:0008203 cholesterol metabolic process | TAS PMID:9659902 Complementation cloning of S2P, a gene encoding a putative m... | MODIFY | Summary: S2P is required for SREBP activation and cholesterol prototrophy. Reason: S2P does not catalyse any step of cholesterol metabolism; it activates SREBPs, which induce cholesterol biosynthetic and uptake genes. The relationship is regulatory and positive, so the claim is re-expressed as positive regulation of cholesterol biosynthetic process (a lateral correction), which the gene already carries by IDA. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:9659902 The human S2P gene was cloned by complementation of mutant CHO cells that cannot cleave SREBPs at Site-2 and are cholesterol auxotrophs. PMID:9659902 SREBPs are membrane-bound transcription factors that activate genes regulating cholesterol metabolism. |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA for membrane. Reason: Correct but general; S2P is an integral Golgi membrane protein. Refine to Golgi membrane. Proposed replacements: Golgi membrane Supporting Evidence: PMID:9659902 S2P defines a new family of polytopic membrane proteins that contain an HEXXH sequence characteristic of zinc metalloproteases. Reactome:R-HSA-1655851 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol. |
| GO:0016020 membrane | TAS PMID:9659902 Complementation cloning of S2P, a gene encoding a putative m... | MODIFY | Summary: S2P is a polytopic membrane protein. Reason: Correct but general; refine to Golgi membrane. Proposed replacements: Golgi membrane Supporting Evidence: PMID:9659902 S2P defines a new family of polytopic membrane proteins that contain an HEXXH sequence characteristic of zinc metalloproteases. 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. |
| GO:0030968 endoplasmic reticulum unfolded protein response | TAS Reactome:R-HSA-381119 | ACCEPT | Summary: Reactome UPR pathway: S2P releases ATF6, ATF6B and CREB3-family transducers. Reason: S2P performs the releasing cleavage for several ER stress transducers (ATF6, ATF6B, OASIS/CREB3L1, BBF2H7/CREB3L2, CREB3L3), so 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:11163209 Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. |
| 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. 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 | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (PTN004417004) for membrane protein intracellular domain proteolysis. Reason: Core process: S2P cleaves within the transmembrane segment to release the cytosolic domain of SREBP/ATF6. Node placement in the S2P clade is sound; the target's own experimental evidence is among the sources. Supporting Evidence: PMID:10805775 Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. PMID:8674110 The second, not regulated by sterols, occurs within the first transmembrane domain. |
| GO:0031293 membrane protein intracellular domain proteolysis | IGI PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | ACCEPT | Summary: Genetic interaction with hamster S2P (O54862) in CHO M19 cells: S2P is required for ATF6 release. Reason: Core process. Supporting Evidence: PMID:11163209 ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. 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:0034976 response to endoplasmic reticulum stress | IGI PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | MODIFY | Summary: S2P-deficient cells fail to induce GRP78 under ER stress. Reason: True but general; the role is the second cleavage of ATF6 in the UPR. Refine to ATF6-mediated unfolded protein response, already carried by the gene. Proposed replacements: ATF6-mediated unfolded protein response Supporting Evidence: PMID:11163209 Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. PMID:11163209 We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis. |
| GO:0034976 response to endoplasmic reticulum stress | ISS GO_REF:0000024 | MODIFY | Summary: ISS from hamster S2P (O54862). Reason: As for the IGI row. Proposed replacements: ATF6-mediated unfolded protein response Supporting Evidence: PMID:11163209 Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. |
| 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 during the UPR. Reason: S2P performs the releasing cleavage of ATF6; 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 Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. |
| 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. Reason: Core process. 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 Reactome:R-HSA-420818 S2P catalyzes the second of these, cleaving the ATF6-alpha S1P cleavage product within its transmembrane domain. |
| 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: S2P cleavage releases the active SREBP transcription factor, so the effect is positive; refine to positive regulation of cholesterol biosynthetic process, already carried by IDA. 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. |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IDA PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | ACCEPT | Summary: S2P is required for release of active SREBPs and hence for lipid synthesis. Reason: S2P catalyses the obligatory activating cleavage of SREBP-1/-2; its loss causes cholesterol auxotrophy. The positive-regulation term is the established convention for the S1P/S2P proteases. Supporting Evidence: PMID:11163209 We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis. PMID:19361614 Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids. PMID:9659902 The human S2P gene was cloned by complementation of mutant CHO cells that cannot cleave SREBPs at Site-2 and are cholesterol auxotrophs. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | MARK AS OVER ANNOTATED | Summary: S2P is required for ATF6-dependent GRP78 induction. Reason: Transcriptional activation is carried out by the released SREBP and ATF6 N-terminal domains. S2P is upstream of transcription by two steps (cleavage, then nuclear import and DNA binding by the substrate), so this term over-states its role; the specific process terms (ATF6-mediated UPR, positive regulation of cholesterol biosynthesis) capture it. Supporting Evidence: PMID:11163209 Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. 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:0051604 protein maturation | EXP PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | MODIFY | Summary: S2P cleavage converts membrane-bound ATF6 into its mature, nuclear form. Reason: Correct but general: the maturation is achieved by peptide-bond cleavage, i.e. protein processing (a descendant of protein maturation). Proposed replacements: protein processing 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 was blocked completely in cells lacking S2P and partially in cells lacking S1P. |
| GO:0051604 protein maturation | IDA PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | MODIFY | Summary: S2P cleavage converts membrane-bound ATF6 into its mature, nuclear form. Reason: As for the EXP row; refine to protein processing. Proposed replacements: protein processing Supporting Evidence: PMID:11163209 ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. |
| GO:0070977 bone maturation | IMP PMID:27380894 MBTPS2 mutations cause defective regulated intramembrane pro... | KEEP AS NON CORE | Summary: MBTPS2 missense variants cause X-linked osteogenesis imperfecta with defective RIP of OASIS, ATF6 and SREBP and reduced collagen secretion. Reason: S2P is required for bone maturation via activation of OASIS/CREB3L1 and related factors in osteoblasts. A genuine physiological role, but downstream of the core intramembrane protease activity. Supporting Evidence: PMID:27380894 Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. PMID:27380894 These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894 Also, proband osteoblasts have broadly defective differentiation. |
| GO:0140537 transcription regulator activator activity | IGI PMID:11163209 ER stress induces cleavage of membrane-bound ATF6 by the sam... | MODIFY | Summary: S2P is required to convert ATF6 into an active transcription factor. Reason: S2P activates ATF6 and SREBPs by proteolytic release, but GO represents an enzyme acting on a regulator by its catalytic activity; a protease is not annotated as a transcription-regulator activator because its product is a transcription factor. Re-express as metalloendopeptidase activity, already carried by EXP/IBA/IEA/TAS. Proposed replacements: metalloendopeptidase activity 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:9659902 S2P defines a new family of polytopic membrane proteins that contain an HEXXH sequence characteristic of zinc metalloproteases. |
| GO:1905897 regulation of response to endoplasmic reticulum stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA (PTN000330396, deep M50 node seeded by Arabidopsis S2P) for regulation of response to ER stress. Reason: Activation of membrane-bound bZIP ER stress transducers by S2P is conserved between plants (bZIP17/28) and animals (ATF6, CREB3 family), so the human protein lies within the clade that inherited this role and there is no evidence of loss. In human the specific mechanism is better described by ATF6-mediated unfolded protein response; the regulatory framing is kept as non-core. Supporting Evidence: PMID:11163209 Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. 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. |
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Download this section (compressed HTML)Q: Should S2P (and S1P) carry GO:0032933 SREBP signaling pathway? In human, mouse and rat that term is held by SCAP, INSIG1/2, SREBF1/2 and ERLIN1/2 but by no protease, whereas the ATF6 pathway term GO:0036500 is annotated to both proteases.
Q: Why do different hypomorphic MBTPS2 alleles give mainly cutaneous (IFAP, KFSD, Olmsted) or mainly skeletal (OI19) disease, and do they impair processing of SREBP, ATF6 and CREB3L1 to different extents?
Q: Does S2P cleave substrates beyond the bZIP transcription factors, for example other type II membrane proteins with Asn-Pro-containing transmembrane helices, and how does it recognise S1P-trimmed substrates?
Experiment: Reconstitute purified human S2P in proteoliposomes with S1P-trimmed SREBP2, ATF6 and CREB3L1 transmembrane substrates and measure cleavage kinetics for wild-type and IFAP/OI19 patient variants to relate residual substrate-specific activity to phenotype.
Experiment: Perform unbiased N-terminomics or proteomics of membrane-released fragments in MBTPS2-knockout versus rescued cells to identify additional physiological S2P substrates.
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