Cell Metabolism
Volume 19, Issue 4, 1 April 2014, Pages 605-617
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Article
Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5

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Highlights

  • Lysine glutarylation is a protein posttranslational modification

  • SIRT5 can catalyze the enzymatic removal of lysine glutarylation

  • Proteomic analyses identify a link between lysine glutarylation and metabolism

  • Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal

Summary

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.

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These authors contributed equally to this work

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Present address: Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark