SREBP signaling — sterol-regulated ER-to-Golgi escort and two-step cleavage of SREBP; SCAP/INSIG/MBTPS1/MBTPS2/SREBF1/SREBF2

The SREBP pathway couples membrane sterol levels to transcription of the genes for cholesterol and fatty-acid synthesis and LDL uptake. SREBP precursors (SREBF1 and SREBF2) are ER-membrane proteins whose N-terminal basic helix-loop-helix leucine-zipper transcription factor domain is held on the cytosolic face of the ER. Their C-terminal regulatory domain binds the WD-repeat domain of SCAP, which carries a sterol-sensing domain and escorts SREBP from the ER to the Golgi in COPII vesicles. When ER cholesterol is high, cholesterol binding to SCAP and oxysterol (25-hydroxycholesterol) binding to the ER-resident INSIG proteins (INSIG1, INSIG2) lock SCAP-SREBP into an INSIG-bound complex that the COPII coat cannot recognise, so SREBP stays in the ER. When sterols fall, SCAP is released, SCAP-SREBP is packaged into COPII vesicles and moves to the Golgi. There SREBP is cleaved sequentially: site-1 protease (MBTPS1, a subtilisin-like serine protease) cuts in the luminal loop, and site-2 protease (MBTPS2, an intramembrane zinc metalloprotease) then cuts within the first transmembrane segment. The released N-terminal fragment enters the nucleus and activates genes bearing sterol regulatory elements, including HMGCR, LDLR and INSIG1 itself, closing a negative feedback loop. In mammals SREBF2 preferentially drives cholesterol synthesis, the SREBF1c transcript fatty-acid synthesis, and SREBF1a both.

Derived from the RGD Pathway Ontology diagram PW:0000753 as the pilot for the RGD_PATHWAY_ONTOLOGY project's diagram->module route. The RGD diagram supplied the boundary, members and topology; GO terms were then chosen against each protein's experimental GO annotations in QuickGO and, for SCAP, against its gene review (sterol sensor activity GO:0032935 for sensing, with cholesterol as the sensed sterol, PMID:17428920, and cargo receptor activity GO:0038024 for the COPII escort; INSIG1 and INSIG2 oxysterol binding GO:0008142 IDA and protein sequestering activity GO:0140311 IDA; MBTPS1 serine-type endopeptidase activity GO:0004252 IDA/EXP; MBTPS2 metalloendopeptidase activity GO:0004222 EXP; SREBF1 DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228 IDA). Each step is backed by the primary papers that defined it (all abstract-only in the publications cache) and cross-checked against the human GO-CAM gomodel:6205c24300000880, which models six of the seven gene products with matching functions (each module annoton links the model activity it corresponds to under gocam_associations); the INSIG process term (GO:0036316) was taken from that model. The model also contains AKT1 (GO:0004674) and PCK1 (GO:0106264): AKT1 activates PCK1, which phosphorylates INSIG1/2 and lowers their sterol binding (PMID:32322062, one study in hepatocellular carcinoma cells). They are left out of this module because their reported effect opposes retention rather than carrying it out, and because the evidence is a single cancer-cell report. That GO-CAM omits SCAP, which is therefore the one step here without curated GO-CAM support, and includes KPNB1 for SREBP nuclear import, a step this module leaves out until it is reviewed. Gene reviews of all seven members are in a separate PR, and PANTHER family ids are deliberately omitted (gene products are named directly) until their families are checked against the PANTHER member index. Downstream SREBP target genes (HMGCR, LDLR, FASN and others) are outputs, not parts, of this module; the cholesterol and fatty-acid biosynthesis modules are its downstream neighbours.