MBTPS1

MBTPS1 (SKI-1/S1P) is a Ca2+-dependent subtilisin-like serine protease that initiates regulated intramembrane proteolysis of membrane-anchored transcription factors and other precursors, thereby coupling proteolytic maturation to lipid metabolism, the unfolded protein response, and viral glycoprotein processing (PMID:10644685, PMID:19202076). The enzyme matures through multiple sequential autocatalytic prosegment cleavages within the ER, with prosegment fragments retained as tight-binding inhibitors, and cleaves substrates after nonbasic residues using P/P' determinants defined for SREBP-2-like sequences (PMID:10644685). After maturation it undergoes ectodomain shedding and an internal alternate-translation event (at Met990) to generate membrane-bound stumps that modulate its processing of ATF6; mature and processed forms localize predominantly to the Golgi, traffic to endosomal/lysosomal compartments, and are excluded from the cell surface by a transmembrane-domain trafficking determinant (PMID:17623657). MBTPS1 is a non-redundant, cell-autonomous activator of the ATF6-dependent UPR in non-hematopoietic cells, where its loss reduces ER chaperones GRP78 and GRP94 and sensitizes to experimental colitis (PMID:19202076). Through the SREBP lipogenic axis, MBTPS1 activity is required for hepatitis C virus genome replication and infectious particle production, acting upstream of HMG-CoA reductase and through LDLR/NPC1L1-dependent and SREBP-independent routes (PMID:22626636, PMID:25573299), and its cleavage of arenavirus glycoprotein precursors in dendritic cells is essential for persistent viral infection (PMID:21402360). Osteocyte-specific MBTPS1 also mediates bone-to-muscle cross-talk, with its deletion increasing slow-twitch muscle mass, contractile force, and regeneration markers without altering muscle MBTPS1 expression (PMID:26719336).

1. 2000 High

   Established the fundamental enzymology of MBTPS1 — whether it is a bona fide protease and how it selects cleavage sites — by defining it as a Ca2+-dependent subtilisin-like proteinase with autocatalytic prosegment processing and substrate residue requirements.

   Evidence Biochemical characterization in LoVo cells with recombinant enzyme, mass spectrometry cleavage-site mapping, synthetic peptide processing, and site-directed mutagenesis

   PMID:10644685

   Open questions at the time

   • Physiological substrate repertoire beyond SREBP-2 and pro-BDNF mimicking peptides not defined here
   • No structural model of the catalytic domain
   • In-cell relevance of prosegment-mediated inhibition not quantified
2. 2007 High

   Resolved how the enzyme matures and where it acts by mapping sequential autocatalytic cleavages, ectodomain shedding, an alternate-translation-derived C-terminal fragment, and Golgi-predominant trafficking that feeds back on ATF6 processing.

   Evidence Site-directed mutagenesis, in vitro transcription/translation, N-terminal sequencing, mass spectrometry, and confocal microscopy with deletion analysis

   PMID:17623657

   Open questions at the time

   • Functional role of stumps St-1/St-2 in regulating substrate choice incompletely defined
   • Mechanism by which the transmembrane domain dictates trafficking not detailed
3. 2009 High

   Demonstrated the in vivo, cell-type-specific physiological requirement for MBTPS1 by showing it is non-redundantly needed in non-hematopoietic cells for the ATF6-dependent UPR and protection from colitis.

   Evidence ENU-induced hypomorphic allele, DSS colitis model, GRP78/GRP94 Western blots, and bone marrow chimeras

   PMID:19202076

   Open questions at the time

   • Hypomorphic allele leaves residual activity, so null phenotype not assessed
   • Direct link between ATF6 cleavage and colitis protection inferred from chaperone levels
4. 2011 High

   Connected MBTPS1 protease activity to host control of viral infection by showing dendritic-cell MBTPS1 cleaves arenavirus glycoprotein precursors and is required for persistent, but not acute, LCMV infection.

   Evidence Hypomorphic Mbtps1 allele, LCMV persistent infection model, organ-specific viral titers, and bone marrow-derived dendritic cell analysis

   PMID:21402360

   Open questions at the time

   • Why persistence and not acute infection depends on Mbtps1 not fully explained
   • Direct biochemical cleavage of arenavirus GP precursor not reconstituted here
5. 2012 Medium

   Showed MBTPS1 enzymatic activity is essential for HCV production via the SREBP lipogenic pathway, identifying it as a pharmacological antiviral target acting upstream of HMG-CoA reductase.

   Evidence PF-429242 inhibitor with dose-response in HCV replicon and HCVcc (JFH-1) assays, comparison with statins, and lipid droplet staining

   PMID:22626636

   Open questions at the time

   • Single lab; pharmacological inhibitor specificity not orthogonally confirmed
   • Direct SREBP processing events in this system not measured
6. 2015 Medium

   Refined MBTPS1's role across the HCV lifecycle by distinguishing an SREBP/LDLR/NPC1L1-dependent contribution to early infection from an SREBP-independent contribution.

   Evidence PF-429242 inhibition with HCV early-step assays and LDLR/NPC1L1 expression analysis

   PMID:25573299

   Open questions at the time

   • Molecular basis of the SREBP-independent mechanism unidentified
   • Single lab, inhibitor-based evidence
7. 2015 Medium

   Revealed a non-cell-autonomous endocrine role by showing osteocyte-specific MBTPS1 deletion enhances slow-twitch muscle mass, force, and regeneration through bone-to-muscle cross-talk.

   Evidence Osteocyte Cre-lox conditional knockout, muscle contractile force measurement, histology of centralized nuclei, qPCR, and microarray

   PMID:26719336

   Open questions at the time

   • The osteocyte-derived signaling factor mediating the muscle effect not identified
   • Relevant MBTPS1 substrate in osteocytes not defined

• The complete physiological substrate repertoire and the structural basis of MBTPS1 substrate selection across its UPR, lipogenic, viral, and endocrine roles remain unresolved.
• No unifying structural model linking active-site to nonbasic-residue specificity
• Mediator of osteocyte-to-muscle cross-talk unidentified
• SREBP-independent antiviral mechanism uncharacterized