Reactive oxygen species (ROS) and other free radicals are generated from endogenous metabolite processes and from exposure to the exogenous environment [1,2]. A basal level of free radicals is essential for maintaining normal biological processes, whereas a high level of free radicals results in continuous and accumulative ‘oxidative damage’ [3]. Cells and the entire organism have developed a spectrum of defense mechanisms for protecting against reactive metabolites to achieve the subtle balance between the production and the elimination of ROS [4]. Imbalances between ROS formation and the cellular antioxidant capacity due to enhanced ROS generation or a dysfunctional antioxidant system leads to oxidative stress, with subsequent damage to cellular proteins, lipids and DNA; consequently, oxidative stress eventually causes various biological catastrophes, such as inflammation, carcinogenesis, degenerative diseases, and aging [5].

NF-E2-related factor 2 (Nrf2), a member of the bZIP family, is an important antioxidant effector of the organism. In a normal redox environment, Nrf2 exists mainly in the cytoplasm [6]. However, when cellular homeostasis is disrupted, Nrf2 translocate to the nucleus to activate the transcription of ARE-containing genes [7]. Nrf2 activity is regulated tightly through a complex system, including negative regulators, such as Keap1, β-TrCP and GSK-3, and transcription related factors, such as small Maf (sMaf) and Bach1 [[8], [9], [10], [11]]. Keap1 suppresses Nrf2 transcriptional activity by specifically binding to the evolutionarily conserved amino-terminal regulatory domain of Nrf2 in the cytoplasm, resulting in Nrf2 degradation mediated by the ubiquitin-proteasome pathway; however, when electrophilic agents modify Keap1, Nrf2 is released from Keap1 and transported from the cytoplasm to the nucleus to potentiate the ARE response [12,13]. Furthermore, nuclear export and import of Nrf2 are regulated. Keap1 can itself translocate to the nucleus and bind to Nrf2 in the nucleus, which mediates Nrf2 nuclear export and causes Nrf2 degradation in the cytoplasm. So Keap1 also can regulate Nrf2 through nuclear export and import, it represents another Keap1-mediated Nrf2 repressive pathway [14,15].

Sirt6, a member of the sirtuin family that is mainly localized to the nucleus, is a NAD+-dependent deacetylase [16] and mono-ADP ribosyltransferase [17]. Sirt6 regulates multiple biological processes, such as longevity, metabolism, and stress defense [[18], [19], [20]]. Specifically, under oxidative stress, Sirt6 deacetylates H3K56Ac to promote genomic stability and stimulates PARP1 to enhance double-strand DNA break (DSB) repair by mono-ADP-ribosylating PARP1 [17,21]. Since both Sirt6 and Nrf2 have protective effects under oxidative stress, we have investigated whether specific interactions between Sirt6 and Nrf2 occur as part of the antioxidative function. In this study, we found that Sirt6 exerted antioxidative effects by regulating the Nrf2 protein level.