Sterol O-acyltransferase 2-Insulin-induced gene 1 interaction (ACAT2-INSIG1 interaction)

Sterol O-acyltransferase 2 (ACAT2) is an endoplasmic reticulum (ER) membrane enzyme primarily expressed in the liver and intestine, where it catalyzes the conversion of free cholesterol into cholesteryl esters for lipoprotein assembly [1, 2, 4]. The interaction between ACAT2 and Insulin-induced gene 1 (INSIG1) serves as a critical regulatory mechanism for maintaining cellular cholesterol homeostasis [3, 6]. INSIG1 acts as an adaptor protein that recruits the E3 ubiquitin ligase GP78 (AMFR) to ACAT2, facilitating its ubiquitination and subsequent proteasomal degradation when cellular lipid levels are low [1, 3]. Conversely, high levels of cholesterol and fatty acids induce reactive oxygen species (ROS) that oxidize ACAT2 at Cys-277, preventing its ubiquitination and leading to protein stabilization and increased esterification activity [3, 4]. This interaction is a significant therapeutic target because ACAT2-mediated esterification contributes to the formation of atherogenic lipoproteins and the progression of diseases such as atherosclerosis, hypercholesterolemia, and certain cancers [11, 12, 16]. Modulating this interaction or directly inhibiting ACAT2 offers a strategy to reduce circulating cholesterol levels and prevent lipid-induced toxicity [1, 17].

Other names

SOAT2-INSIG1 interactionAcyl-CoA:cholesterol acyltransferase 2-Insulin-induced gene 1 interactionACAT2-INSIG1-GP78 complexACAT2-INSIG1-AMFR complex

Regulation of ACAT2 protein stability via INSIG1-mediated recruitment of the E3 ubiquitin ligase GP78 (AMFR), leading to ubiquitination and proteasomal degradation of the enzyme.