INSIG1 (O15503) review notes

Deep research status

2026-10-18: just deep-research human INSIG1 --provider falcon was tried once and failed
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INSIG1 (insulin-induced gene 1, rat CL-6) is a polytopic ER membrane protein, PANTHER
PTHR15301:SF11 (family PTHR15301, INSIG). The human gene is on 7q36
PMID:9268630.
INSIG1 and INSIG2 are 59% identical paralogs with six transmembrane helices
PMID:12242332.
Distant bacterial homolog MvINS (Mycobacterium) gives the six-TM fold
PMID:26160948.

Discovery: INSIG1 binds the sterol-sensing domain of SCAP and retains SCAP/SREBP in the ER
PMID:12202038.
Sterols induce the SCAP-INSIG1 interaction; SCAP(Y298C) cannot bind and escapes regulation
PMID:12202038.
Mechanism: INSIG is required for sterol inhibition of Sar1-dependent Sec23/24 (COPII) binding to the
MELADL signal of SCAP PMID:15899885;
sterols and Insig render MELADL inaccessible PMID:17428919.
Insigs lower the cholesterol concentration needed for the SCAP conformational change
PMID:12963821.
Feedback: INSIG1 transcription needs nuclear SREBPs (unlike INSIG2)
PMID:12242332;
at high expression INSIG1 (not INSIG2) blocks SCAP movement even without exogenous sterols
PMID:12242332.
Free INSIG1 is ubiquitinated (Lys156/158) and degraded upon sterol depletion; binding to SCAP protects it
PMID:16399501.
Asp205 (juxtamembrane, TM4) is required for SCAP binding and HMGCR degradation
PMID:16606821.
PAQR3 competes with INSIG1 for SCAP and tethers SCAP-SREBP to Golgi
PMID:26311497.

Oxysterols (25-hydroxycholesterol) act by binding Insigs; TM3/TM4 are important
PMID:17428920.
Structure of human SCAP-INSIG2-25HC (paralog) shows 25HC sandwiched between SCAP S4-S6 and Insig TM3/4
PMID:33446483.
PCK1 (single lab, HCC cells) phosphorylates INSIG1 Ser207, which reduces sterol binding and releases SCAP
PMID:32322062.
The IDA rows for oxysterol binding/retention from this paper are consistent with the Brown-Goldstein work.

INSIG1 binds the HMGCR sterol-sensing domain and triggers its degradation
PMID:12535518.
INSIG1 bridges gp78/AMFR (E3) and VCP to HMGCR
PMID:16168377.
Both Insigs bind TRC8/RNF139; gp78 binds INSIG1 but not INSIG2
PMID:22143767.
RNF145 also binds INSIG1/2 PMID:29374057.
Insigs are adaptors recruiting ACAT2 to gp78 PMID:28604676.
GO: GO:1990756 ubiquitin-like ligase-substrate adaptor activity fits; there is no GO process term for
regulated (non-quality-control) ERAD of a native enzyme. GO:0036503 "ERAD quality control pathway"
is defined for misfolded/aberrant proteins, so it was not proposed.

protein binding: SCAP rows MODIFY -> GO:0140311; AMFR/HMGCR rows MODIFY -> GO:1990756; P450
(PGRMC1 study) and HuRI Y2H rows REMOVE (uninformative).
ER (GO:0005783): MODIFY -> ER membrane (GO:0005789), all rows, same in INSIG2.
cholesterol biosynthetic process / cholesterol metabolic process: MODIFY -> GO:0045541 negative
regulation of cholesterol biosynthetic process (INSIG does not perform the synthesis). Same in INSIG2.
cellular response to insulin stimulus IBA: MARK_AS_OVER_ANNOTATED. The node's donor is rat Insig1
IEP (expression induction, PMID:19299314 per QuickGO); insulin regulates INSIG1/2 transcription in
opposite directions (INSIG2a is repressed, PMID:12624180), so it is not a conserved protein function. Same in INSIG2.
regulation of transcription by RNA pol II NAS: MARK_AS_OVER_ANNOTATED (indirect, via SREBP processing).
Core: GO:0140311, GO:0008142, GO:0036316, GO:1901303, GO:0032937, GO:0005789; GO:1990756 (HMGCR ERAD).
GO-CAM 6205c24300000880 models INSIG1 as oxysterol binding + protein sequestering activity in
GO:0036316 at the ER membrane, consistent with this review.