INSIG2
Description
The INSIG2 (insulin induced gene 2) is a protein-coding gene located on chromosome 2.
INSIG2, also known as Insulin-induced gene 2, is a protein that is encoded by the INSIG2 gene in humans. It is highly similar to INSIG1 and both proteins are located in the endoplasmic reticulum. INSIG2 and INSIG1 bind to SCAP (SREBP cleavage-activating protein) and block the processing of SREBPs (sterol regulatory element–binding proteins) by preventing SCAP from transporting SREBPs to the Golgi apparatus. The regulation of INSIG2 is complex. Insulin activates the INSIG2 promoter through phosphorylated SAP1a. Akt mediates the suppression of Insig2a, a liver-specific transcript encoding INSIG2. MCHR2 has been observed to decrease INSIG2 levels. Insig2 is upregulated under hypoxic conditions and is associated with pancreatic cancer malignancy. A novel 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) response element in the INSIG2 promoter region was identified, which specifically binds to the retinoid X receptor and vitamin D receptor (VDR) heterodimer, leading to VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells, suggesting potential roles in other lipogenic cell types that express VDR. Insig deficiency in mice resulted in a marked accumulation of cholesterol precursors in the skin, along with an increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase protein. This led to hair and skin defects that were corrected by topical simvastatin, an inhibitor of reductase.
INSIG2 is an oxysterol-binding protein that plays a crucial role in regulating cholesterol synthesis. It acts as a feedback mechanism by controlling the transport of SCAP (SREBP cleavage-activating protein) from the endoplasmic reticulum (ER) to the Golgi apparatus and by regulating the degradation of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase). INSIG2 binds to oxysterols, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol, which modulates its interaction with SCAP. In the presence of oxysterols, INSIG2 interacts with SCAP, retaining the SCAP-SREBP complex in the ER and preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi. When sterol levels are low or when PCK1 phosphorylates INSIG2, oxysterol binding is reduced, disrupting the INSIG2-SCAP interaction and allowing the SCAP-SREBP complex to move to the Golgi, where SREBPs are processed and translocated to the nucleus. Additionally, INSIG2 regulates cholesterol synthesis by regulating the degradation of HMGCR. It initiates the sterol-mediated ubiquitin-mediated ER-associated degradation (ERAD) of HMGCR by recruiting the reductase to the ubiquitin ligase RNF139.
INSIG2 is also known as INSIG-2.
