Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5

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

doi:10.1016/j.cmet.2014.03.014

Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5

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

387 Citations (Scopus)

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 K_glu sites in 191 proteins and showed that K_glu 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 language	English
Journal	Cell Metabolism
Volume	19
Issue number	4
Pages (from-to)	605–617
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2014.03.014
Publication status	Published - 1 Apr 2014

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Tan, M., Peng, C., Anderson, K. A., Xie, Z., Chhoy, P., Dai, L., Park, J., Chen, Y., Huang, H., Zhang, Y., Ro, J., Wagner, G. R., Green, M. F., Madsen, A. S., Schmiesing, J., Peterson, B. S., Xu, G., Ilkayeva, O. R., Muehlbauer, M. J., ... Zhao, Y. (2014). Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5. Cell Metabolism, 19(4), 605–617. https://doi.org/10.1016/j.cmet.2014.03.014

Tan, M, Peng, C, Anderson, KA, Xie, Z, Chhoy, P, Dai, L, Park, J, Chen, Y, Huang, H, Zhang, Y, Ro, J, Wagner, GR, Green, MF, Madsen, AS, Schmiesing, J, Peterson, BS, Xu, G, Ilkayeva, OR, Muehlbauer, MJ, Braulke, T, Mühlhausen, C, Backos, DS, Olsen, CA, McGuire, PJ, Pletcher, SD, Lombard, DB, Hirschey, MD & Zhao, Y 2014, 'Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5', Cell Metabolism, vol. 19, no. 4, pp. 605–617. https://doi.org/10.1016/j.cmet.2014.03.014

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title = "Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5",

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.",

author = "Minjia Tan and Chao Peng and Anderson, {Kristin A} and Zhongyu Xie and Peter Chhoy and Lunzhi Dai and Jeongsoon Park and Yue Chen and He Huang and Yi Zhang and Jennifer Ro and Wagner, {Gregory R} and Green, {Michelle F} and Madsen, {Andreas Stahl} and Jessica Schmiesing and Peterson, {Brett S} and Guofeng Xu and Ilkayeva, {Olga R} and Muehlbauer, {Michael J} and Thomas Braulke and Chris M{\"u}hlhausen and Backos, {Donald S} and Olsen, {Christian Adam} and McGuire, {Peter J} and Pletcher, {Scott D} and Lombard, {David B} and Hirschey, {Matthew D} and Yingming Zhao",

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T1 - Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5

AU - Tan, Minjia

AU - Peng, Chao

AU - Anderson, Kristin A

AU - Xie, Zhongyu

AU - Chhoy, Peter

AU - Dai, Lunzhi

AU - Park, Jeongsoon

AU - Chen, Yue

AU - Huang, He

AU - Zhang, Yi

AU - Ro, Jennifer

AU - Wagner, Gregory R

AU - Green, Michelle F

AU - Madsen, Andreas Stahl

AU - Schmiesing, Jessica

AU - Peterson, Brett S

AU - Xu, Guofeng

AU - Ilkayeva, Olga R

AU - Muehlbauer, Michael J

AU - Braulke, Thomas

AU - Mühlhausen, Chris

AU - Backos, Donald S

AU - Olsen, Christian Adam

AU - McGuire, Peter J

AU - Pletcher, Scott D

AU - Lombard, David B

AU - Hirschey, Matthew D

AU - Zhao, Yingming

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.cmet.2014.03.014

DO - 10.1016/j.cmet.2014.03.014

M3 - Journal article

C2 - 24703693

SN - 1550-4131

VL - 19

SP - 605

EP - 617

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5

Abstract

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