Lysine Glutarylation Is a Protein Post-Translational Modification Regulated by SIRT5

By M. Tan, Chao Peng, K. A. Anderson, Peter Chhoy, Zhongyu Xie, Lunzhi Dai, J. Park, Yue Chen, He Huang, Yi Zhang and 18 more. Cell Metabolism, 2014

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We report the identification and characterization of a five-carbon protein post-translational modification (PTM) called lysine glutarylation (Kglu). 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 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 academia 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.

Subfields: Epidemiology, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/6e4835f2ead90a240a79f078fe507eefee548ff7

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