SREBF2 (human, Q12772) review notes

Deep research status

2026-10-18: just deep-research human SREBF2 --provider falcon was tried once and failed
with Exception: Failed to authenticate (Falcon/Edison key not authorised). No
-deep-research-*.md file exists for this gene; the review below is built from the
UniProt record, the cached GOA-cited publications, and a few extra primary papers and
reviews cached with ai-gene-review fetch-pmid (PMID:8674110, PMID:11994399).

SREBP-2 is a 1141-residue bHLH-Zip transcription factor made as an ER membrane-bound
precursor PMID:7903453.
Three domains: N-terminal bHLH-Zip transcription factor (~480 aa), a hairpin of two TM
segments with a short luminal loop, and a C-terminal regulatory domain (~590 aa) that
binds SCAP [PMID:11994399 "Each SREBP precursor of about 1150 amino acids is organized
into three domains"; PMID:9242699 "Complex formation occurs when cells express only the
COOH-terminal domain of either SREBP-2 or SCAP, indicating that the complex forms between
the two COOH-terminal domains."].
Sterol-regulated two-step proteolysis releases the N-terminal domain: S1P in the luminal
loop, then S2P inside TM1 [PMID:8674110 "The first, regulated by sterols, occurs in the
lumenal loop. The second, not regulated by sterols, occurs within the first
transmembrane domain."; "The liberated NH2-segment enters the nucleus and activates genes
controlling cholesterol synthesis and uptake."].
SCAP escorts SREBP from ER to Golgi in COPII vesicles in sterol-depleted cells; sterols
promote SCAP-INSIG binding and ER retention PMID:12202038; INSIG-2 behaves the same way
PMID:12242332.
Golgi anchoring by PAQR3 promotes processing PMID:26311497. TRC8/RNF139 binds SREBP-2 and SCAP and hampers ER exit PMID:19706601.
Nuclear form is imported by importin-beta as a dimer (Reactome R-HSA-1655831, R-HSA-2065550)
and is rapidly degraded by the ubiquitin-proteasome system PMID:11477106.

Binds SRE-1 like SREBP-1a and activates SRE reporters PMID:7903453.
Preferential activator of cholesterol synthesis genes and LDLR; weak on lipogenic
SRE-like promoters; binds but does not activate an E-box reporter [PMID:12177166
"cholesterogenic genes containing classic SREs in their promoters are strongly and
efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c"; "SREBP-2 was
inactive in spite of its ability to bind to the E-box"]; PMID:11994399.
In vivo, nSREBP-2 transgenic liver: 75-fold HMGCR mRNA increase, 28-fold cholesterol
synthesis increase PMID:11994399.
Activates INSIG1 (feedback loop) PMID:12242332.
Coactivators: CBP/p300 KIX domain and Mediator MED15/ARC105 KIX-like domain
PMID:16799563. HNF-4 binds SREBP-2 and potentiates it
PMID:12855700.
Context-specific repression: nSREBP-2 represses ABCA1 via an E-box in endothelial cells
PMID:15358760; it is also the proposed LRP1 repressor in vascular smooth muscle
[PMID:19098903, indirect knockdown evidence]. These are non-core.

PMID:12941800 (Vidal et al. 2003) characterises "SRBP-2", an SR31747A-binding protein of
206 aa homologous to the sterol isomerase HSI/EBP (i.e. an EBP-like protein), not SREBP-2.
The abstract states it explicitly: "The 1142-bp cDNA was found to encode a 206 amino acid
protein not related to SRBP-1." The four GOA rows drawn from it (ER, nucleus, cytoplasm,
NOT C-8 sterol isomerase activity) therefore rest on a different protein. The location
claims happen to be true of SREBF2 from other evidence, so they are judged on the claim;
the NOT isomerase row is removed.
PMID:24912190 (mitophagy RNAi screen) does not mention SREBF2 in the cached text; the HMP
rows are screen hits, and the text centres on SREBF1.
PMID:15358760 abstract reports oscillatory (not laminar) flow activating SREBP2; the NAS
"cellular response to laminar fluid shear stress" row is not supported by the abstract.
PMID:32497488 is an SREBF1 IFAP-syndrome paper; the abstract does not show SREBF2 assays,
but the SREBF2 IMP rows (TF activity, nucleus) are biologically correct and are accepted
in deference to the curator, who read the full text.

gocams/6205c24300000880 (Regulation of cholesterol biosynthesis by SREBP and retention by
SREBP-SCAP complex, human) models SREBF2 with GO:0000981 part_of GO:0045542 in the
nucleus, consistent with the core function chosen here.