The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China; Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China; School of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China.
Redox Biol. 2019 Feb;21:101111. doi: 10.1016/j.redox.2019.101111. Epub 2019 Jan 15.
Caenorhabditis elegans NRF (NF-E2-related factor)/CNC (Cap'n'collar) transcription factor, Skinhead-1 (SKN-1), is conservatively critical for promoting phase II detoxification gene expressions in response to oxidative stress. SKN-1 activity is controlled by well-known phosphorylation and recently-reported O-GlcNAcylation. Whether other kinds of posttanslational modifications of SKN-1 occur and influence its function remains elusive. Here, we found arginines 484 and 516 (R484/R516) of SKN-1 were asymmetrically dimethylated by PRMT-1. Oxidative stress enhanced the binding of PRMT-1 to SKN-1. Consequently, asymmetrical dimethylation of arginines on SKN-1 was elevated. Loss of prmt-1 or disruption of R484/R516 dimethylation decreased the enrichment of SKN-1 on the promoters of SKN-1-driven phase II detoxification genes, including gamma-glutamine cysteine synthetase gcs-1, glutathione S-transferases gst-7 and gst-4, which resulted in reduced ability of worms to defense against oxidative stress. These findings have important implications for investigating the physiological and pathological functions of arginine methylation on conserved NRF/CNC transcription factors in human diseases related to oxidative stress response.
秀丽隐杆线虫 NRF（NF-E2 相关因子）/CNC（Cap'n'collar）转录因子 Skinhead-1（SKN-1）保守地对于促进氧化应激响应中的 II 相解毒基因表达至关重要。SKN-1 的活性受到广泛认可的磷酸化和最近报道的 O-GlcNAc 酰化的调控。SKN-1 是否发生其他类型的翻译后修饰以及这些修饰是否影响其功能仍然难以捉摸。在这里，我们发现 SKN-1 的精氨酸 484 和 516（R484/R516）被 PRMT-1 不对称二甲基化。氧化应激增强了 PRMT-1 与 SKN-1 的结合。因此，SKN-1 上精氨酸的不对称二甲基化增加。prmt-1 的缺失或 R484/R516 二甲基化的破坏降低了 SKN-1 在 SKN-1 驱动的 II 相解毒基因启动子上的富集，包括γ-谷氨酰胺半胱氨酸合成酶 gcs-1、谷胱甘肽 S-转移酶 gst-7 和 gst-4，这导致线虫抵抗氧化应激的能力降低。这些发现对于研究与氧化应激反应相关的人类疾病中保守的 NRF/CNC 转录因子上精氨酸甲基化的生理和病理功能具有重要意义。
