State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Cell Metab. 2021 Oct 5;33(10):2004-2020.e9. doi: 10.1016/j.cmet.2021.09.008.
Nonalcoholic steatohepatitis (NASH) is an advanced stage of nonalcoholic fatty liver disease (NAFLD) with serious consequences that currently lacks approved pharmacological therapies. Recent studies suggest the close relationship between the pathogenesis of NAFLD and the dysregulation of RNA splicing machinery. Here, we reveal death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is markedly upregulated in the livers of both NAFLD/NASH patients and NAFLD/NASH diet-fed mice. Hepatic deletion of DRAK2 suppresses the progression of hepatic steatosis to NASH. Comprehensive analyses of the phosphoproteome and transcriptome indicated a crucial role of DRAK2 in RNA splicing and identified the splicing factor SRSF6 as a direct binding protein of DRAK2. Further studies demonstrated that binding to DRAK2 inhibits SRSF6 phosphorylation by the SRSF kinase SRPK1 and regulates alternative splicing of mitochondrial function-related genes. In conclusion, our findings reveal an indispensable role of DRAK2 in NAFLD/NASH and offer a potential therapeutic target for this disease.
非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪性肝病（NAFLD）的晚期阶段，目前缺乏批准的药物治疗方法，后果严重。最近的研究表明，NAFLD 的发病机制与 RNA 剪接机制的失调密切相关。在这里，我们发现凋亡诱导激酶 2（DRAK2）在 NAFLD/NASH 患者和 NAFLD/NASH 饮食喂养的小鼠肝脏中显著上调。肝脏中 DRAK2 的缺失抑制了肝脂肪变性向 NASH 的进展。磷酸化蛋白质组和转录组的综合分析表明 DRAK2 在 RNA 剪接中起关键作用，并确定剪接因子 SRSF6 是 DRAK2 的直接结合蛋白。进一步的研究表明，与 DRAK2 的结合抑制了 SRSF 激酶 SRPK1 对 SRSF6 的磷酸化，并调节与线粒体功能相关基因的可变剪接。总之，我们的研究结果揭示了 DRAK2 在 NAFLD/NASH 中的不可或缺作用，并为该疾病提供了一个潜在的治疗靶点。
