INSIG1
Description
The INSIG1 (insulin induced gene 1) is a protein-coding gene located on chromosome 7.
Insulin induced gene 1, also known as INSIG1, is a protein which in humans is encoded by the INSIG1 gene. INSIG1 is short for insulin-induced gene 1; it is located on chromosome 7 (7q36). This human gene encodes for a transmembrane protein of 277 amino acids with probably 6 transmembrane domains. It is localized in the endoplasmic reticulum (ER) and seems to be expressed in all tissues, especially in liver. This gene is called an insulin-induced gene because the molecule insulin can regulate it. Importantly, the protein encoded by this gene plays a critical role in regulating cholesterol concentrations in cells.
== Function == INSIG1 plays an important role in the SREBP-mediated regulation of cholesterol biosynthesis: by binding to the sterol-sensing domain of SCAP (SREBP cleavage activating protein) it makes the SCAP/SREBP complex stay longer in the ER, thus prohibiting SCAP from carrying activated SREBP to the golgi complex. This ultimately blocks SREBP from acting as a transcription factor for the SRE in the promoter region of the HMG-CoA-reductase gene and results in a decreased expression of HMG-CoA-reductase. INSIG1 also binds to the sterol-sensing domain of HMG-CoA-reductase, resulting in the enzyme's increased degradation. Both functions require the binding of INSIG1 protein via the same site.
INSIG1 is an oxysterol-binding protein that plays a key role in regulating cholesterol synthesis. It acts as a negative regulator by controlling both the transport of SCAP from the endoplasmic reticulum (ER) to the Golgi apparatus and the degradation of HMGCR. INSIG1 binds to oxysterols, including 25-hydroxycholesterol, which regulates its interaction with SCAP and the retention of the SCAP-SREBP complex in the ER. This prevents the processing of SREBPs (SREBF1/SREBP1 and SREBF2/SREBP2) and their subsequent nuclear translocation. Sterol deprivation or phosphorylation by PCK1 can disrupt this interaction, leading to the release of the SCAP-SREBP complex and the activation of SREBPs. Additionally, INSIG1 regulates cholesterol synthesis by controlling the degradation of HMGCR. It initiates the ubiquitin-mediated degradation of HMGCR through the recruitment of the reductase to the ubiquitin ligases AMFR/gp78 and/or RNF139. When lipid levels are low, INSIG1 also regulates the degradation of SOAT2/ACAT2 by recruiting AMFR/gp78 to initiate ubiquitin-mediated degradation.
INSIG1 is also known as CL6.
