TY - JOUR
T1 - Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation
AU - Wang, Yong-Jian
AU - Bian, Yan
AU - Luo, Jie
AU - Lu, Ming
AU - Xiong, Ying
AU - Guo, Shu-Yuan
AU - Yin, Hui-Yong
AU - Lin, Xu
AU - Li, Qin
AU - Chang, Catherine C. Y.
AU - Chang, Ta-Yuan
AU - Li, Bo-Liang
AU - Song, Bao-Liang
N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
AB - 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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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U2 - 10.1038/ncb3551
DO - 10.1038/ncb3551
M3 - RGC 21 - Publication in refereed journal
C2 - 28604676
SN - 1465-7392
VL - 19
SP - 808
EP - 819
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 7
ER -
