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- Title
Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2.
- Authors
Zhou, Zhang-Sen; Li, Mei-Xin; Liu, Jie; Jiao, Hengwu; Xia, Jing-Ming; Shi, Xiong-Jie; Zhao, Huabin; Chu, Liping; Liu, Jingrong; Qi, Wei; Luo, Jie; Song, Bao-Liang
- Abstract
Insig-2 is an ER membrane protein negatively controlling lipid biosynthesis. Here, we find that Insig-2 is increased in the tissues, including liver, but unaltered in the muscle of gp78-deficient mice. In hepatocytes and undifferentiated C2C12 myoblasts, Insig-2 is ubiquitylated on Cys215 by gp78 and degraded. However, the C215 residue is oxidized by elevated reactive oxygen species (ROS) during C2C12 myoblasts differentiating into myotubes, preventing Insig-2 from ubiquitylation and degradation. The stabilized Insig-2 downregulates lipogenesis through inhibiting the SREBP pathway, helping to channel the carbon flux to ATP generation and protecting myotubes from lipid over-accumulation. Evolutionary analysis shows that the YECK (in which C represents Cys215 in human Insig-2) tetrapeptide sequence in Insig-2 is highly conserved in amniotes but not in aquatic amphibians and fishes, suggesting it may have been shaped by differential selection. Together, this study suggests that competitive oxidation-ubiquitylation on Cys215 of Insig-2 senses ROS and prevents muscle cells from lipid accumulation. The protein Insig-2 negatively regulates lipid biosynthesis and is short-lived in liver cells but stable in muscle cells. Here, the authors show that in muscle cells producing reactive oxygen species, there is increased oxidation compared to ubiquitination of Insig-2, stabilising Insig-2 and reducing lipid biosynthesis.
- Subjects
UBIQUITINATION; LIVER cells; CYSTEINE; OXIDATION; MEMBRANE proteins; MYOBLASTS; MUSCLE cells
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-14231-w