insig

Insig refers to a pair of conserved endoplasmic reticulum membrane proteins that play a central role in cellular cholesterol homeostasis. The name derives from insulin-induced genes, as the proteins were first identified in studies of insulin-responsive tissues. The two human genes encoding these proteins are INSIG1 and INSIG2.

Insig proteins are integral or closely associated with the endoplasmic reticulum membrane and are characterized by multiple transmembrane domains. They function as part of the sterol-sensing machinery that coordinates the activity of sterol regulatory element-binding proteins (SREBPs), which control transcription of many genes involved in cholesterol biosynthesis and uptake. In the presence of high sterol levels, Insig binds to SCAP, retaining the SREBP-SCAP complex in the endoplasmic reticulum and preventing SREBP activation. When sterol levels fall, the SCAP-SREBP complex is allowed to move to the Golgi, where SREBP is processed into an active transcription factor that promotes expression of cholesterol biosynthetic genes, including HMG-CoA reductase and LDL receptor.

In addition to regulating SREBP processing, Insig proteins are involved in the degradation and turnover of HMG-CoA reductase, linking sterol status to multiple steps in the cholesterol pathway. INSIG1 and INSIG2 have overlapping but distinct expression patterns across tissues, with INSIG2 existing in alternative splice forms that can influence its activity in different cell types.

clinically, dysregulation of Insig function can contribute to disorders of lipid metabolism, and the Insig-SCAP-SREBP axis is an active area of research for therapies aimed at lowering cholesterol and treating metabolic syndrome.