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EMBO J. 2014 Jun 17;33(12):1304-20. doi: 10.1002/embj.201387224. Epub 2014 Apr 25.

Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.

Author information

1
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.
2
School of Pharmacy East China University of Science and Technology, Shanghai, China.
3
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.
4
Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital Zhejiang Cancer Center, Hangzhou, China.
5
Department of Radiotherapy, Zhejiang Province Cancer Hospital Zhejiang Cancer Center, Hangzhou, China.
6
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.
7
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.
8
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.

Abstract

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.

KEYWORDS:

G6PD; SIRT2; acetylation; nicotinamide adenine dinucleotide phosphate; reactive oxygen species

PMID:
24769394
PMCID:
PMC4194121
DOI:
10.1002/embj.201387224
[Indexed for MEDLINE]
Free PMC Article

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