MBTPS1 (S1P / SKI-1 / PCSK8) review notes

Provenance / process

• 2026-10-18: Deep research via Falcon (just deep-research-falcon human MBTPS1) attempted once and
  failed at authentication ("Exception: Failed to authenticate"; the Edison/Falcon key returns 403).
  No -deep-research-*.md file exists for this gene; these notes were compiled manually from the
  cached publications (mostly abstract-only), the UniProt record and Reactome.
• Additional PMIDs cached for this review: 8674110, 10644685, 10944850, 16417584, 32857899
  (plus 10805775/10419520 used for MBTPS2).

Identity and structure

• 1052 aa type I membrane protein: signal peptide 1-17, propeptide 18-186, lumenal domain
  187-998 containing the peptidase S8 (subtilisin) domain 190-472 with the Asp218/His249/Ser414
  charge-relay triad, a single TM helix 999-1021 and short cytosolic tail (UniProt).
• "Belongs to the peptidase S8 family" (UniProt); a member of the proprotein convertase
  subtilisin/kexin family (PCSK8), but unlike the furin-like PCs it cleaves after non-basic residues
  with Arg/Lys at P4 (R-X-[hydrophobic]-X↓ / RX(L/V/I)X motifs) PMID:9990022.
• Ca2+-dependent serine protease PMID:10644685.
• Zymogen; propeptide removed by intramolecular autocatalytic cleavage after Leu186 (RRLL186)
  PMID:10944850; prosegment fragments remain associated and inhibit the enzyme
  PMID:10644685.

Localization

• Processing of proSKI-1 in the ER; mature enzyme in Golgi and punctate endosome-like structures;
  a 98 kDa form is shed into the medium [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."; "Late along the secretory pathway some of the
  membrane-bound enzyme is shed into the medium as a 98-kDa form."].
• Golgi is the site of SREBP/ATF6 cleavage PMID:12782636.
• A 2022 report claims a mitochondrial pool forming a complex with ETFA/ETFB PMID:35362222.
  Single study; S1P has a canonical ER signal peptide and lumenal catalytic domain, so how a
  mitochondrial pool arises is unexplained. Treated as non-core.

Substrates / functions (pleiotropic)

1. SREBP-1/-2: first (luminal-loop) cleavage in regulated intramembrane proteolysis (RIP)
   [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."]. Sterol regulation is exerted through SCAP/INSIG
   transport control rather than on S1P itself.
2. ATF6/ATF6B: first cleavage during the UPR PMID:11163209. AEBSF inhibition of S1P blocks ATF6 cleavage PMID:12782636.
3. CREB3 family (OASIS/CREB3L1, BBF2H7/CREB3L2, CREB-H/CREB3L3, LUMAN/CREB3) [PMID:16417584
   "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-8874204, R-HSA-8874206]. BBF2H7 activation drives TANGO1/SEC23A expression and mega-vesicle
   collagen export PMID:30046013.
4. GNPTAB α/β precursor: S1P cleavage activates GlcNAc-1-phosphotransferase, required for M6P
   tagging of lysosomal enzymes PMID:21719679. LYSET/TMEM251 is required for efficient processing
   PMID:36096887.
5. FAM20C propeptide removal, required for FAM20C secretion and kinase activity in biomineralization
   PMID:34349020.
6. Pro-BDNF, and (literature, not cached here) viral glycoproteins of arenaviruses (Lassa, LCMV GPC)
   and Crimean-Congo hemorrhagic fever virus — host-pathogen role, not curated here.

Disease

• Spondyloepiphyseal dysplasia Kondo-Fu type (SEDKF): ~1% residual MBTPS1 gives skeletal dysplasia
  and elevated plasma lysosomal enzymes but near-normal lipids PMID:30046013; second patient PMID:32857899.
• CAOP syndrome (cataract, alopecia, oral mucosal disorder, psoriasis-like) PMID:35362222.

Curation decisions summary

• Core MF: serine-type endopeptidase activity (GO:0004252); generic endopeptidase / serine-type
  peptidase IEAs -> MODIFY to GO:0004252.
• Core location: Golgi membrane; ER membrane (zymogen maturation), extracellular (shed form),
  mitochondrion kept as non-core. ER lumen TAS rows -> MODIFY to ER membrane (the protein is a
  type I membrane protein whose catalytic domain faces the lumen).
• Process: membrane protein intracellular domain proteolysis (RIP) and protein processing;
  ATF6-mediated UPR; positive regulation of cholesterol biosynthesis (via SREBP) replaces the
  generic "regulation of" TAS row (mouse Mbtps1 already carries GO:0045542).
• proteolysis rows -> MODIFY to GO:0031293 + GO:0016485 (pleiotropic, both supported).
• protein maturation (GNPTAB) -> MODIFY to GO:0016485 protein processing.
• protein binding (FAM20C; ETFA/ETFB) -> REMOVE (uninformative).
• mitotic G2 DNA damage checkpoint signaling (IEA from mouse) -> MARK_AS_OVER_ANNOTATED: downstream
  of CREB3L1 activation, not an S1P activity.
• NEW: protein autoprocessing (GO:0016540) for propeptide autocatalysis.
• Comparator check for GO:0032933 SREBP signaling pathway: carried in human/mouse/rat by SCAP,
  INSIG1/2, SREBF1/2, ERLIN1/2 but by no S1P/S2P protease (QuickGO query 2026-10-18); not proposed
  as NEW, raised as a suggested question instead.

2026-11-03 ORGANELLES batch 4 (mitochondrion rows)

Rows: GO:0005739 IDA (PMID:35362222) and IEA (GO_REF:0000044, SL-0173), both located_in, both KEEP_AS_NON_CORE
already. No sub-compartment rows.

Checks (full text of PMID:35362222 cached):
- Fractionation separated mitochondria from ER and Golgi PMID:35362222, so not the crude-pellet/MAM case.
- Protease protection PMID:35362222; partners ETFA/ETFB are matrix.
- UniProt Mitochondrion is curated from PMID:35362222 (ECO:0000269); the IEA mapping is sound.

Outcome: both rows stay KEEP_AS_NON_CORE, reasons record the check. No GO:0005759 row: the matrix reading
(one protease-protection assay, one study) conflicts with the curated ER/Golgi single-pass type I topology
and lumenal protease domain, and protection past the OMM does not separate inner membrane from matrix.