Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.
Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular reductant. G6PD deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. Here, we show that G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re-expression of wild-type G6PD, but not the K403 acetylation mimetic mutant, rescues cells from oxidative injury. Moreover, we show that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. We also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China.
Yi-Ping
YP
Wang
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China.
Li-Sha
LS
Zhou
School of Pharmacy East China University of Science and Technology, Shanghai, China.
Yu-Zheng
YZ
Zhao
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China.
Shi-Wen
SW
Wang
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China.
Lei-Lei
LL
Chen
Key Laboratory of Synthetic Biology, Bioinformatics Center and Laboratory of Systems Biology, Institute of Plant Physiology and Ecology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
Li-Xia
LX
Liu
Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital Zhejiang Cancer Center, Hangzhou, China.
Zhi-Qiang
ZQ
Ling
Department of Radiotherapy, Zhejiang Province Cancer Hospital Zhejiang Cancer Center, Hangzhou, China.
Fu-Jun
FJ
Hu
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China.
Yi-Ping
YP
Sun
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China.
Jing-Ye
JY
Zhang
Key Laboratory of Synthetic Biology, Bioinformatics Center and Laboratory of Systems Biology, Institute of Plant Physiology and Ecology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
Chen
C
Yang
School of Pharmacy East China University of Science and Technology, Shanghai, China.
Yi
Y
Yang
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
Yue
Y
Xiong
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Kun-Liang
KL
Guan
Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College College of Life Science Fudan University, Shanghai, China yedan@fudan.edu.cn.
Dan
D
Ye
D000107:Acetylation; D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D009249:NADP / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D056565:Sirtuin 2 / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D009249:NADP; D005954:Glucosephosphate Dehydrogenase; C538729:ELP3 protein, human; D051548:Histone Acetyltransferases; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2
G6PD; SIRT2; acetylation; nicotinamide adenine dinucleotide phosphate; reactive oxygen species