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

Authors

  • Yi-Ping Wang,

    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
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  • Li-Sha Zhou,

    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
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  • Yu-Zheng Zhao,

    1. School of Pharmacy, East China University of Science and Technology, Shanghai, China
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  • Shi-Wen Wang,

    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
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  • Lei-Lei Chen,

    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
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  • Li-Xia Liu,

    1. 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
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  • Zhi-Qiang Ling,

    1. Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
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  • Fu-Jun Hu,

    1. Department of Radiotherapy, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
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  • Yi-Ping Sun,

    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
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  • Jing-Ye Zhang,

    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
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  • Chen Yang,

    1. 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
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  • Yi Yang,

    1. School of Pharmacy, East China University of Science and Technology, Shanghai, China
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  • Yue Xiong,

    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. Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA
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  • Kun-Liang Guan,

    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. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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  • Dan Ye

    Corresponding author
    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
    • Corresponding author. Tel: +86 21 5423 7834; Fax: +86 21 5423 7450; E-mail: yedan@fudan.edu.cn

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  • Correction added on 26 May 2014, after first online publication. In the article title, “KAT9/SIRT2” was corrected to “SIRT2 and KAT9”.
  • See also: LE Wu & DA Sinclair (June 2014)

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.

Synopsis

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The pentose phosphate pathway plays an important role in the oxidative stress response by supplying the reductant NADPH. SIRT2-mediated deacetylation and activation of the glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in this pathway, stimulates the production of cytosolic NADPH to counteract oxidative damage.

  • K403 acetylation decreases G6PD activity by inhibiting dimer formation.
  • SIRT2 and KAT9/ELP3 regulate G6PD K403 acetylation.
  • Regulation of G6PD K403 acetylation modulates NADPH homeostasis and cell survival during oxidative stress.

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