Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2

Zhang-Sen Zhou, Mei-Xin Li, Jie Liu, Hengwu Jiao, Jing-Ming Xia, Xiong-Jie Shi, Huabin Zhao, Liping Chu, Jingrong Liu, Wei Qi, Jie Luo and Bao-Liang Song ()
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Zhang-Sen Zhou: Wuhan University
Mei-Xin Li: Wuhan University
Jie Liu: Wuhan University
Hengwu Jiao: Wuhan University
Jing-Ming Xia: Wuhan University
Xiong-Jie Shi: Wuhan University
Huabin Zhao: Wuhan University
Liping Chu: ShanghaiTech Universiy
Jingrong Liu: ShanghaiTech Universiy
Wei Qi: ShanghaiTech Universiy
Jie Luo: Wuhan University
Bao-Liang Song: Wuhan University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14231-w

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