2. Academic Validation
  3. Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation

Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation

  • Nat Cell Biol. 2017 Jul;19(7):808-819. doi: 10.1038/ncb3551.
Yong-Jian Wang 1 2,  Yan Bian 1,  Jie Luo 3,  Ming Lu 1,  Ying Xiong 1,  Shu-Yuan Guo 4,  Hui-Yong Yin 4,  Xu Lin 4,  Qin Li 1,  Catherine C Y Chang 5,  Ta-Yuan Chang 5,  Bo-Liang Li 1,  Bao-Liang Song 3
Affiliations

Affiliations

  • 1 The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • 2 Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China.
  • 3 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China.
  • 4 Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 5 Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA.
PMID: 28604676 DOI: 10.1038/ncb3551
Abstract

Ubiquitin linkage to cysteine is an unconventional modification targeting protein for degradation. However, the physiological regulation of cysteine ubiquitylation is still mysterious. Here we found that ACAT2, a cellular Enzyme converting Cholesterol and fatty acid to cholesteryl esters, was ubiquitylated on Cys277 for degradation when the lipid level was low. gp78-Insigs catalysed Lys48-linked polyubiquitylation on this Cys277. A high concentration of Cholesterol and fatty acid, however, induced cellular Reactive Oxygen Species (ROS) that oxidized Cys277, resulting in ACAT2 stabilization and subsequently elevated cholesteryl esters. Furthermore, ACAT2 knockout mice were more susceptible to high-fat diet-associated Insulin resistance. By contrast, expression of a constitutively stable form of ACAT2 (C277A) resulted in higher Insulin sensitivity. Together, these data indicate that lipid-induced stabilization of ACAT2 ameliorates lipotoxicity from excessive Cholesterol and fatty acid. This unconventional cysteine ubiquitylation of ACAT2 constitutes an important mechanism for sensing lipid-overload-induced ROS and fine-tuning lipid homeostasis.

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