SREBF1 (human, P36956) review notes

Deep research status

• 2026-10-18: just deep-research human SREBF1 --provider falcon was attempted once and failed
  with Exception: Failed to authenticate (Falcon/Edison key not authorised). No
  -deep-research-*.md file exists for this gene; these notes were compiled manually from
  cached publications (publications/PMID_*.md), the UniProt record and Reactome entries.

Identity and architecture

• SREBP-1, a bHLH-ZIP transcription factor of 1147 aa, cloned from human cells as the protein that
  binds SRE-1 of the LDLR promoter PMID:8402897. SRE-1 is a direct repeat, not a canonical E-box PMID:8402897.
• Dual DNA specificity (E-box and SRE-1) set by an atypical tyrosine in the basic region
  PMID:7739539. Study used rat ADD1;
  human data on the same Tyr->Arg switch in PMID:12177166.
• UniProt topology: N-terminal transactivation + bHLH-ZIP (bHLH 323-373) cytosolic domain 1-487,
  two TM helices (488-508, 548-568) with a short luminal loop (S1P site 530-531), C-terminal
  regulatory domain 569-1147 that binds SCAP. S2P site 490-491. Processed chain PRO_0000314029
  (1-490) is the nuclear form.

Activation pathway (SREBP signaling)

• Precursor in ER/nuclear envelope; cleaved in sterol-depleted cells to a soluble nuclear
  fragment [PMID:8156598 "is synthesized as a 125 kd precursor that is attached to the nuclear
  envelope and endoplasmic reticulum"; "In sterol-depleted cells, the membrane-bound precursor is
  cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that
  translocates to the nucleus"].
• Two sequential cleavages (shown with SREBP-2) PMID:8674110.
• SCAP escort and INSIG retention PMID:12202038; INSIG-1/2 act the same on SREBP-1a PMID:12242332.
• Human genetics: IFAP2 mutations at residues 527/528/530 block S1P cleavage PMID:32497488.
• Nuclear form turns over fast via ubiquitin-proteasome PMID:11477106.
• PCK1-INSIG phosphorylation releases SCAP-SREBP in HCC cells PMID:32322062.

Isoforms

• 1a vs 1c differ in exon 1 (acidic activation domain) PMID:9062341.
• 1a activates cholesterol + fatty acid genes; 1c much weaker and lipogenic-biased
  PMID:9062341; human HepG2 reporters
  PMID:12177166.
• Review [PMID:11994399 "SREBP-1a is a potent activator of all SREBP-responsive genes, including
  those that mediate the synthesis of cholesterol, fatty acids, and triglycerides."; "SREBP-1c
  preferentially enhances transcription of genes required for fatty acid synthesis but not
  cholesterol synthesis."].
• 1c is transcriptionally induced by LXR and insulin, repressed by glucagon/cAMP and PUFA
  [PMID:11994399 "Three factors selectively regulate the transcription of SREBP-1c: liver
  X-activated receptors (LXRs), insulin, and glucagon."; PMID:11090130]. Insulin induction in
  adipocytes PMID:9421459.
• SREBP-1aDelta / 1cDelta (P36956-5/-6) are truncated at 470 and lack the membrane anchor; nuclear
  and constitutively active (UniProt; PMID:18267114, not cached).

GOA observations

• 128 rows. Many IEA "response to X" rows from rat Srebf1 (Ensembl Compara) reflect regulation of
  Srebf1 expression by nutrients/hormones/xenobiotics, not participation of the protein in the
  response. Marked as over-annotations except insulin (SREBP-1c mediates insulin's lipogenic
  transcription) kept non-core.
• GO:0004879 nuclear receptor activity (IDA, PMID:23610160) is categorically wrong for a bHLH-ZIP
  protein; the nuclear receptor in that paper is SF1 (NR5A1). The derived IEA GO:0030522 follows.
• GO:0090209 negative regulation of triglyceride metabolic process (PMID:28483554) has the wrong
  sign for SREBF1: the abstract shows SREBF1 induction drives steatosis and miR-192 suppresses it
  by suppressing SREBF1.
• Mitophagy rows (PMID:24912190) come from an RNAi screen; the block was bypassed by exogenous
  lipids, so the effect is indirect through lipogenesis.
• Process terms like cholesterol metabolic process / lipid biosynthetic process are modified to
  the positive-regulation terms, since SREBF1 is a transcriptional regulator and not an enzyme.
• GO-CAM gocams/6205c24300000880 models SREBF1 as GO:0000981 part_of GO:0045542; the review
  accepts both.

Isoform modelling decision (2026-10-18)

The functional differences between SREBF1 forms (1a, 1c, the anchorless Delta
variants and the nuclear fragment) are preferences of target choice and regulation,
not exclusive activities, so the related GO terms are annotated to the gene as a
whole and functional_isoforms carries no isoform_specific_terms. The third core
function (the ER/Golgi precursor as pathway substrate) deliberately has no molecular
function, matching SREBF2: the precursor does not bind DNA.