Tan, Minjia3; Peng, Chao10; Anderson, Kristin A.11; Chhoy, Peter11; Xie, Zhongyu10; Dai, Lunzhi10; Park, Jeongsoon12; Chen, Yue10; Huang, He10; Zhang, Yi3; Ro, Jennifer12; Wagner, Gregory R.11; Green, Michelle F.11; Madsen, Andreas Stahl1; Schmiesing, Jessica13; Peterson, Brett S.11; Xu, Guofeng10; Ilkayeva, Olga R.11; Muehlbauer, Michael J.11; Braulke, Thomas13; Mühlhausen, Chris13; Backos, Donald S.8; Olsen, Christian Adam1; McGuire, Peter J.9; Pletcher, Scott D.12; Lombard, David B.12; Hirschey, Matthew D.11; Zhao, Yingming3
1 Department of Chemistry, Technical University of Denmark2 Organic Chemistry, Department of Chemistry, Technical University of Denmark3 Chinese Academy of Sciences4 University of Chicago5 Duke University6 University of Michigan7 University Medical Center Hamburg-Eppendorf8 University of Colorado9 US National Institute of Health10 University of Chicago11 Duke University12 University of Michigan13 University Medical Center Hamburg-Eppendorf
We report the identification and characterization of a five-carbon protein posttranslational 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 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.
Cell Metabolism, 2014, Vol 19, Issue 4, p. 605-617