T-2 Toxin Induces Oxidative Stress at Low Doses Via ATF3∆Zip2a/2b-Mediated Ubiquitination and Degradation of Nrf2

Abstract Background: T-2 toxin is mainly produced by Fusarium species, which is an extremely toxic mycotoxin to humans and animals. It is well known that T-2 toxin induces oxidative stress, but the molecular mechanism is still unknown. Results: In this study, we found that T-2 toxin significantly promoted ROS accumulation in MCF-7 cells at low doses which maintains cell viability at least 80%. Further analysis showed that T-2 toxin downregulated the expression of the master regulator of antioxidant defense gene, Nrf2, and its targeted antioxidant genes. Overexpression of Nrf2 or its target gene HO1 significantly blocked the ROS accumulation in MCF-7 cells under T-2 toxin treatment. Moreover, we found that T-2 toxin downregulated the antioxidant genes via inducing the expression of ATF3∆Zip2a/2b. Importantly, overexpression of ATF3∆Zip2a/2b promoted the ubiquitination and degradation of Nrf2. Conclusions: This work demonstrated that T-2 toxin induced ROS accumulation via ATF3∆Zip2a/2b mediated ubiquitination and degradation of Nrf2, which provided a new insight into the mechanism of T-2 toxin-induced oxidative stress.