期刊
CELL METABOLISM
卷 19, 期 4, 页码 605-617出版社
CELL PRESS
DOI: 10.1016/j.cmet.2014.03.014
关键词
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资金
- NIH [GM105933, CA160036, RR020839, GM101171, CA177925, AG000114]
- Nancy and Leonard Florsheim Family Fund
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2012ZX09301001-007]
- Natural Science Foundation of China [31370814]
- Shanghai Pujiang Program [13PJ1410300]
- American Heart Association [12SDG8840004, 12IRG9010008]
- Edward Mallinckrodt Jr. Foundation
- Ellison Medical Foundation
- National Institutes of Health [AA022146, AG045351]
- Duke O'Brien Center for Kidney Research [5P30DK096493-02]
- NCI [CA059365-19]
- Danish Independent Research Council-Technology and Production Sciences (Sapere Aude grant) [12-132328]
- Danish Independent Research Council-Natural Sciences (Steno grant) [10-080907]
- Villum Foundation
- Carlsberg Foundation
- German Research Foundation (Deutsche Forschungsgemeinschaft) [MU1778/3-1]
- NIH/NIGMS [5T32GM007105-40]
We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (K-glu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191 proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and increases our understanding of the deacylase SIRT5.
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