Chem Res Toxicol. 2018 May 21;31(5):380-387. doi: 10.1021/acs.chemrestox.8b00062. Epub 2018 Apr 23.
Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response signaling pathway is a major mechanism for the cellular defense against oxidative stress. Arsenite, a widespread contaminant in drinking water, is known to induce oxidative stress and activate the Nrf2-dependent signaling pathway through the stabilization of the Nrf2 protein by inhibiting its ubiquitination via the Cul3-Rbx1-Keap1 (cullin 3, RING-box 1, and Kelch-like ECH-associated protein 1) E3 ubiquitin ligase, and its degradation by the 26S proteasome, though the underlying mechanism, remains elusive. In the present study, we demonstrated that arsenite could bind to the RING finger domain of Rbx1 in vitro and in cells, which led to the suppression of Cul3-Rbx1 E3 ubiquitin ligase activity, thereby impairing the Nrf2 ubiquitination and activating the Nrf2-induced antioxidant signaling pathway. Our finding provided novel insight into arsenic toxicity by uncovering a distinct mechanism accounting for arsenite-induced Nrf2 activation.
核因子红细胞 2 相关因子 2（Nrf2）抗氧化反应信号通路的激活是细胞抵御氧化应激的主要机制。砷是饮用水中广泛存在的污染物，已知通过抑制 Cul3-Rbx1-Keap1（Cullin 3、RING-box 1 和 Kelch-like ECH-associated protein 1）E3 泛素连接酶对 Nrf2 蛋白的泛素化及其通过 26S 蛋白酶体的降解，从而稳定 Nrf2 蛋白，来诱导氧化应激并激活 Nrf2 依赖性信号通路，但潜在机制仍不清楚。在本研究中，我们证明了砷化物可以在体外和细胞内与 Rbx1 的 RING 指结构域结合，从而抑制 Cul3-Rbx1 E3 泛素连接酶的活性，进而损害 Nrf2 的泛素化并激活 Nrf2 诱导的抗氧化信号通路。我们的发现提供了对砷毒性的新见解，揭示了一种解释砷诱导 Nrf2 激活的独特机制。
