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

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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)

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.

Suggested Citation

  • 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 & Bao-Liang Song, 2020. "Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14231-w
    DOI: 10.1038/s41467-019-14231-w
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