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Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation
- Source :
- Nature cell biology. 19(7)
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
Male
Time Factors
Genotype
CHO Cells
Diet, High-Fat
Transfection
03 medical and health sciences
chemistry.chemical_compound
Residue (chemistry)
0302 clinical medicine
Insulin resistance
Cricetulus
Ubiquitin
Oxidizing agent
medicine
Animals
Homeostasis
Humans
Cysteine
Mice, Knockout
biology
Cholesterol
Fatty Acids
Ubiquitination
Cell Biology
Hep G2 Cells
medicine.disease
Cell biology
Mice, Inbred C57BL
Receptors, Autocrine Motility Factor
Disease Models, Animal
030104 developmental biology
Phenotype
chemistry
Biochemistry
Lipotoxicity
Liver
030220 oncology & carcinogenesis
Proteolysis
biology.protein
RNA Interference
Cholesterol Esters
Insulin Resistance
Reactive Oxygen Species
Oxidation-Reduction
Sterol O-Acyltransferase
Subjects
Details
- ISSN :
- 14764679
- Volume :
- 19
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Nature cell biology
- Accession number :
- edsair.doi.dedup.....e05475971b1c49f45cb9e1b9f4d30348