Sirt6 mediates antioxidative functions by increasing Nrf2 abundance

Oxidative stress caused by excess ROS often leads to cellular macromolecule damage and eventually causes various biological catastrophes. Sirt6, a member of the mammalian homolog family of yeast Sir2 NAD+-dependent histone deacetylases, regulates multiple biological processes. Sirt6 exerts antioxidative functions by enhancing DNA repair and DNA end resection. In our study, we found that Sirt6 expression was induced by H2O2 and paraquat (PQ) in cells. When exposed to PQ, the Sirt6+/- C57BL/6 mice showed more serious liver damage and lower survival rate than the Sirt6+/+ mice. The Nrf2 protein levels and the mRNA levels of its target genes in mouse tissues were decreased by Sirt6 deficiency, and Sirt6 overexpression increased the Nrf2 protein content. Moreover, the endogenous H2O2 levels were increased in the tissues of Sirt6-deficient mice and were decreased in Sirt6 overexpression cells. Then, we found that Nrf2 was degraded faster in the Sirt6-deficient mouse embryonic fibroblasts (MEFs) than in the wild type MEFs and that Sirt6 enhanced the protein accumulation of Nrf2 in the nucleus. Lastly, we found that Sirt6 interacted with Nrf2 in co-IP and GST pull-down assays and that Sirt6 overexpression decreased the binding of Nrf2 to Keap1. Taken together, the results of the present study suggest that Sirt6 exerts antioxidative functions by increasing the Nrf2 protein level via Keap1-mediated regulation.