Lysine glutarylation is a protein posttranslational modification regulated by SIRT5

Minjia Tan, Chao Peng, Kristin A. Anderson, Peter Chhoy, Zhongyu Xie, Lunzhi Dai, Jeongsoon Park, Yue Chen, He Huang, Yi Zhang, Jennifer Ro, Gregory R. Wagner, Michelle F. Green, Andreas S. Madsen, Jessica Schmiesing, Brett S. Peterson, Guofeng Xu, Olga R. Ilkayeva, Michael J. Muehlbauer, Thomas BraulkeChris Mühlhausen, Donald S. Backos, Christian A. Olsen, Peter J. McGuire, Scott D. Pletcher, David B. Lombard, Matthew D. Hirschey, Yingming Zhao

Research output: Contribution to journalArticle

337 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)605-617
Number of pages13
JournalCell Metabolism
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2014

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