Chen Ayelet, Feldman Michal, Vershinin Zlata, Levy Dan
The Shraga Segal Department of Microbiology, Immunology and Genetics, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653, Be'er Sheva 84105, Israel.
The Shraga Segal Department of Microbiology, Immunology and Genetics, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653, Be'er Sheva 84105, Israel.
Biochim Biophys Acta. 2016 Feb;1859(2):420-7. doi: 10.1016/j.bbagrm.2016.01.003. Epub 2016 Jan 15.
The protein methyltransferase SETD6 is a key regulator of proliferation and inflammatory processes. However, the role of SETD6 in the regulation of additional cell signaling pathways has not been well studied. Here we show that SETD6 is a negative regulator of the oxidative stress response. Depletion of SETD6 from cells results in elevated Nrf2 levels and a significant increase in Nrf2 antioxidant target gene expression. Using proteomic tools, we uncovered a novel interaction between SETD6 and the oxidative stress sensor DJ1, a protein required for Nrf2-dependent transcription of antioxidant target genes. We show that SETD6 binds DJ1 both in-vitro and in cells but does not methylate DJ1. Under basal conditions, SETD6 and DJ1 are associated at chromatin. Through this interaction, SETD6 inhibits DJ1 activity, which in turn leads to the repression of Nrf2-dependent transcription. In response to oxidative stress, the transcription of Nrf2 antioxidant genes increases. We here show that under this condition, SETD6 mRNA and protein levels are reduced, leading to elevation in Nrf2 expression level and to a weaken interaction between SETD6 and DJ1 at chromatin. Taken together, these findings demonstrate that SETD6 negatively regulates the Nrf2-mediated oxidative stress response through a physical and catalytically independent interaction with DJ1 at chromatin.
蛋白质甲基转移酶SETD6是增殖和炎症过程的关键调节因子。然而，SETD6在调节其他细胞信号通路中的作用尚未得到充分研究。在此，我们表明SETD6是氧化应激反应的负调节因子。从细胞中去除SETD6会导致Nrf2水平升高以及Nrf2抗氧化靶基因表达显著增加。使用蛋白质组学工具，我们发现了SETD6与氧化应激传感器DJ1之间的一种新相互作用，DJ1是Nrf2依赖性抗氧化靶基因转录所必需的蛋白质。我们表明SETD6在体外和细胞中均与DJ1结合，但不会使DJ1甲基化。在基础条件下，SETD6和DJ1在染色质上相关联。通过这种相互作用，SETD6抑制DJ1活性，进而导致Nrf2依赖性转录受到抑制。在氧化应激反应中，Nrf2抗氧化基因的转录增加。我们在此表明，在这种情况下，SETD6的mRNA和蛋白质水平降低，导致Nrf2表达水平升高以及SETD6与DJ1在染色质上的相互作用减弱。综上所述，这些发现表明SETD6通过在染色质上与DJ1进行物理和催化独立的相互作用来负调节Nrf2介导的氧化应激反应。
