Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR (PubMed:12242332, PubMed:12624180, PubMed:16100574). Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:16100574). Binds oxysterol, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (By similarity). In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi (By similarity). Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (By similarity). Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase RNF139 (By similarity). Interacts with SCAP; interaction is direct and only takes place in the presence of sterols; it prevents interaction between SCAP and the coat protein complex II (COPII). Associates with the SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); association is mediated via its interaction with SCAP and only takes place in the presence of sterols. Interacts with RNF139. Interacts with RNF145. Expressed in liver, testis, kidney, spleen, intestine, brain and adrenal gland. Up-regulated in differentiating preadipocytes. Binds oxysterols in a pocket within their transmembrane domains and interacts with SCAP via transmembrane domains 3 and 4. The KxHxx motif mediates association with the coatomer complex. Phosphorylation at Ser-151 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG2 and SCAP, thereby promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes. Polyubiquitinated by AMFR/gp78 at Cys-215 in some tissues such as adipose tissues, undifferentiated myoblasts and liver, leading to its degradation. In differentiated myotubes, Cys-215 oxidation prevents ubiquitination at the same site, resulting in protein stabilization. Oxidized at Cys-215 in differentiated myotubes, preventing ubiquitination at the same site, and resulting in protein stabilization. Knockout mice with a conditional deletion of Insig1 in the liver and a germline deletion of Insig2 overaccumulate cholesterol and triglycerides in liver: despite this accumulation, levels of nuclear sterol regulatory element-binding proteins (SREBPs) are not reduced (PubMed:16100574). The amount of HMGCR is also elevated, caused by impaired degradation of the enzyme (PubMed:16100574). Knockout mice with a germline deletion of both Insig1 and Insig2 die within one day of birth (PubMed:16100574, PubMed:16955138). After 18.5 days of development, embryos lacking both Insig1 and Insig2 show defects in midline facial development, ranging from cleft palate to complete cleft face: middle and inner ear structures are abnormal, but teeth and skeletons are normal (PubMed:16955138). The livers and heads of embryos lacking both Insig1 and Insig2 overproduce sterols, causing a marked buildup of sterol intermediates (PubMed:16955138). Belongs to the INSIG family.