title: Regulation of diacylglycerol acyltransferase 2 protein stability by gp78-associated endoplasmic-reticulum-associated degradation.
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.
authors.affiliation: Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, Chungbuk, Korea.
authors.forename: Kwangman
authors.initials: K
authors.lastname: Choi
authors.forename: Hyeongki
authors.initials: H
authors.lastname: Kim
authors.forename: Hyunju
authors.initials: H
authors.lastname: Kang
authors.forename: So-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Back
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: M Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Park
authors.forename: Jiye
authors.initials: J
authors.lastname: Kim
authors.forename: Sunhong
authors.initials: S
authors.lastname: Kim
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Song
authors.forename: Yura
authors.initials: Y
authors.lastname: Choi
authors.forename: Suui
authors.initials: S
authors.lastname: Lee
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jong Heon
authors.initials: JH
authors.lastname: Kim
authors.forename: Sungchan
authors.initials: S
authors.lastname: Cho
mesh_terms: D045744:Cell Line, Tumor; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D004795:Enzyme Stability; D057809:HEK293 Cells; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D050356:Lipid Metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D060285:Receptors, Autocrine Motility Factor / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase; C555000:AMFR protein, human; D060285:Receptors, Autocrine Motility Factor; D046988:Proteasome Endopeptidase Complex
keywords: E3 ligase; ER-associated degradation (ERAD); diacylglycerol acyltransferase 2 (DGAT2); gp78; triacylglycerol