G6PD Activity Is Regulated By Acetylation To Modulate NADPH Homeostasis During Oxidative Stress

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in oxidative stress response by producing NADPH, the main intracellular reductant. G6PD deficiency is one of the most common hereditary genetic disorders, affecting greater 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. Knock-down 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 stimulate PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. Besides, KAT9/ELP3 is identified as the potential acetyltransferase of K403 of G6PD.Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.