Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase.
Glycolytic enzyme phosphoglycerate mutase (PGAM) plays an important role in coordinating energy production with generation of reducing power and the biosynthesis of nucleotide precursors and amino acids. Inhibition of PGAM by small RNAi or small molecule attenuates cell proliferation and tumor growth. PGAM activity is commonly upregulated in tumor cells, but how PGAM activity is regulated in vivo remains poorly understood. Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. Increased levels of reactive oxygen species stimulate PGAM2 deacetylation and activity by promoting its interaction with SIRT2. Substitution of endogenous PGAM2 with an acetylation mimetic mutant K100Q reduces cellular NADPH production and inhibits cell proliferation and tumor growth. These results reveal a mechanism of PGAM2 regulation and NADPH homeostasis in response to oxidative stress that impacts cell proliferation and tumor growth.
Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai, PR China;
Yanping
Y
Xu
Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai, PR China;
Fulong
F
Li
Authors' Affiliations: Ministry of Education Key Laboratory of Molecular Medicine, and Department of Biochemistry and Molecular Biology, Shanghai Medical College, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences.
Lei
L
Lv
Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai, PR China;
Tingting
T
Li
Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai, PR China;
Xin
X
Zhou
Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland;
Chu-Xia
CX
Deng
Authors' Affiliations: Ministry of Education Key Laboratory of Molecular Medicine, and Department of Biochemistry and Molecular Biology, Shanghai Medical College, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California; and yxiong@email.unc.edu kuguan@ucsd.edu qlei@fudan.edu.cn.
Kun-Liang
KL
Guan
Authors' Affiliations: Ministry of Education Key Laboratory of Molecular Medicine, and Department of Biochemistry and Molecular Biology, Shanghai Medical College, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, yxiong@email.unc.edu kuguan@ucsd.edu qlei@fudan.edu.cn.
Qun-Ying
QY
Lei
Authors' Affiliations: Ministry of Education Key Laboratory of Molecular Medicine, and Department of Biochemistry and Molecular Biology, Shanghai Medical College, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina yxiong@email.unc.edu kuguan@ucsd.edu qlei@fudan.edu.cn.
Yue
Y
Xiong
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009154:Mutation; D009249:NADP / Q000096:biosynthesis; D018384:Oxidative Stress / Q000502:physiology*; D010736:Phosphoglycerate Mutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D056565:Sirtuin 2 / Q000378:metabolism*
D017382:Reactive Oxygen Species; D009249:NADP; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D010736:Phosphoglycerate Mutase