INSIG2 (Q9Y5U4) review notes

Deep research status

• 2026-10-18: Falcon deep research was tried once for INSIG1 in this session and failed at login
  ("Exception: Failed to authenticate"; key not authorised). It was not retried for INSIG2.
  No deep-research file exists. These notes are built from cached primary literature, UniProt and GOA.

Identity and family

• INSIG2 is the paralog of INSIG1 (PANTHER PTHR15301:SF10), a six-TM ER membrane protein with a
  shorter N-terminus PMID:12242332.
• More conserved than INSIG1 across vertebrates PMID:12242332.
• ER location by immunofluorescence PMID:12242332.

Core function 1: sterol-dependent ER retention of SCAP-SREBP

• INSIG2 binds SCAP in a sterol-regulated way and blocks SREBP export
  PMID:12242332.
• Restores sterol block of SCAP budding in a vesicle-formation assay
  PMID:12242332.
• Absolute sterol requirement, and constitutive (SREBP-independent) expression; this is the key
  difference from INSIG1 PMID:12242332.
• Liver-specific Insig-2a transcript is repressed by insulin, allowing SREBP-1c processing
  PMID:12624180.
• Insigs lower cholesterol needed for SCAP conformational change PMID:12963821.

Core function 2: oxysterol binding (best-characterised for INSIG2)

• PMID:17428920; TM3/TM4 needed for oxysterol and Scap binding.
• Cryo-EM human SCAP-INSIG2-25HC PMID:33446483.
• MvINS-based model PMID:26160948.
• PCK1 phosphorylation of INSIG2 Ser151 reduces sterol binding (single lab, HCC) PMID:32322062.

Core function 3: HMGCR ERAD adaptor (TRC8/RNF145 rather than gp78)

• Both Insigs mediate sterol-induced HMGCR binding PMID:22143767.
• INSIG2 does not detectably bind gp78 but binds Trc8 PMID:22143767.
• Asp to Ala in INSIG2 gives the same dual defect as INSIG1 D205A PMID:16606821.
• RNF145 binds Insig-1 and -2 PMID:29374057.
• GO:1990756 ubiquitin-like ligase-substrate adaptor activity proposed as NEW (no GOA row for this on INSIG2).

Annotation decisions (summary; kept identical to INSIG1 for shared PAINT terms)

• 39 protein-binding rows: SCAP rows (PMID:12242332, PMID:17428920) MODIFY -> GO:0140311; HuRI/Rolland
  Y2H rows (incl. RNF5) REMOVE as uninformative.
• ER -> MODIFY to ER membrane; cholesterol biosynthetic/metabolic process -> MODIFY to GO:0045541.
• cellular response to insulin stimulus IBA and response to insulin IEA: MARK_AS_OVER_ANNOTATED (expression
  regulation of the gene, not a protein function; insulin represses Insig-2a).
• response to lipid IEA: MODIFY -> GO:0036315 cellular response to sterol (INSIG2 is a sterol sensor).
• response to fatty acid IEA: MARK_AS_OVER_ANNOTATED (no human evidence that INSIG2 protein acts in a fatty-acid response).
• regulation of transcription by RNA pol II NAS: MARK_AS_OVER_ANNOTATED, as for INSIG1.
• Gene-specific difference vs INSIG1: INSIG2 is not an SREBP target (no feedback induction), has an absolute
  sterol requirement and weaker SCAP affinity; and its ERAD partner is TRC8/RNF145 rather than gp78.
  None of these changes the shared-term verdicts.