Regulation of diacylglycerol acyltransferase 2 protein stability by gp78-associated endoplasmic-reticulum-associated degradation = G78와 ERAD를 통한 DGAT2 단백질의 분해

Abstract

Triacylglycerol (TG) is the major form of stored energy in eukaryotic organisms and is synthesized by diacylglycerol acyltransferase (DGAT) in the endoplasmic reticulum (ER). DGAT2, one of the two DGAT enzymes, is barely detectable in cells, even though its mRNA transcripts are maintained at considerable levels. However, little is known about how DGAT2 expression is altered by protein stability. DGAT2 was highly unstable in cells and was rapidly degraded by proteasomes in an ubiquitin-dependent manner. Deletion mutation analysis identified transmembrane domain 1 (TMD1) as a protein degradation signal. TMD1 is also important for ER localization of DGAT2. Moreover, DGAT2 interacted with p97/VCP, a crucial component of the ER-associated degradation (ERAD) pathway, and polyubiquitinated DGAT2 accumulated following treatment with an ERAD inhibitor. Furthermore, gp78, an E3 ligase involved in ERAD, regulates the degradation of DGAT2 through direct interactions and ubiquitination. Consequently, the stabilization of DGAT2 increased the number of lipid droplets in hepatic cells. Therefore, DGAT2 is regulated by gp78-associated ERAD at the post-translational level. Structured digital abstract DGAT2 physically interacts with gp78 by anti tag coimmunoprecipitation (View interaction) DGAT2 physically interacts with VCP by anti tag coimmunoprecipitation (View interaction) DGAT2, catalyzing the last step in triacylglycerol (TG) synthesis, has drawn attention due to its therapeutic potential for treatment of metabolic diseases. Here, we demonstrated that instability of DGAT2 protein is an additional mechanism for finely controlling the amount of protein in cells. Importantly, we propose gp78-dependent ER-associated degradation (ERAD) as a mechanism of DGAT2 degradation.