Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5

被引：622

作者：

Tan, Minjia ^{[1
,2
]}

Peng, Chao ^{[3
]}

Anderson, Kristin A. ^{[4
]}

Chhoy, Peter ^{[4
]}

Xie, Zhongyu ^{[3
]}

Dai, Lunzhi ^{[3
]}

Park, Jeongsoon ^{[5
,6
]}

Chen, Yue ^{[3
]}

Huang, He ^{[3
]}

Zhang, Yi ^{[1
,2
]}

Ro, Jennifer ^{[7
,8
]}

Wagner, Gregory R. ^{[4
]}

Green, Michelle F. ^{[4
]}

Madsen, Andreas S. ^{[9
]}

Schmiesing, Jessica ^{[10
]}

Peterson, Brett S. ^{[4
]}

Xu, Guofeng ^{[3
]}

Ilkayeva, Olga R. ^{[4
]}

Muehlbauer, Michael J. ^{[4
]}

Braulke, Thomas ^{[10
]}

Muehlhausen, Chris ^{[10
]}

Backos, Donald S. ^{[11
]}

Olsen, Christian A. ^{[9
]}

McGuire, Peter J. ^{[12
]}

Pletcher, Scott D. ^{[7
,8
]}

Lombard, David B. ^{[5
,6
]}

Hirschey, Matthew D. ^{[4
]}

Zhao, Yingming ^{[1
,2
,3
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Chem Prote Ctr, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[3] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA

[4] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27704 USA

[5] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA

[9] Tech Univ Denmark, Dept Chem, DK-2800 Lyngby, Denmark

[10] Univ Med Ctr Hamburg Eppendorf, Childrens Hosp, Dept Biochem, D-20246 Hamburg, Germany

[11] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Computat Chem & Biol Core Facil, Aurora, CO 80045 USA

[12] NHGRI, NIH, Bethesda, MD 20892 USA

来源：

CELL METABOLISM | 2014年 / 19卷 / 04期

基金：

美国国家卫生研究院;

关键词：

CARBAMOYL-PHOSPHATE SYNTHETASE; ACETYL-COENZYME-A; MOUSE MODEL; SUCCINYLATION; IDENTIFICATION; METABOLISM; NUTRIENT; INSIGHTS; DOMAIN;

D O I：

10.1016/j.cmet.2014.03.014

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：605 / 617

页数：13

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