小柯机器人

中国科学院上海药物研究所Jingya Li、Minjia Tan和复旦大学附属中山医院Mingfeng Xia小组合作取得一项新突破。他们的研究发现DRAK2通过srsf6介导的RNA选择性剪接加剧非酒精性脂肪肝(NASH)的进展。该研究于2021年10月5日发表于国际学术期刊《细胞-代谢》杂志。

在本研究中，研究人员揭示了与死亡受体相关蛋白激酶有关的凋亡诱导激酶DRAK2在非酒精性脂肪性肝病(NAFLD)/NASH患者和饮食喂养NAFLD/NASH小鼠的肝脏中显著上调。肝脏DRAK2缺失抑制了肝脂肪变性向NASH的进展。对磷酸化蛋白质组和转录组的综合分析揭示了DRAK2在RNA剪接中的关键作用，并发现剪接因子SRSF6是DRAK2的直接结合蛋白。

进一步的研究表明，结合DRAK2抑制了SRSF激酶SRPK1对SRSF6的磷酸化，并调节了线粒体功能相关基因的选择性剪接。总之，该研究结果揭示了DRAK2在NAFLD/NASH中不可或缺的作用，并为该病提供了潜在的治疗靶点。 

据了解，NASH是NAFLD进展到晚期的形式，其产生严重的后果，目前缺乏针对这类疾病的获批药物。最近的研究表明NAFLD的发病机制与RNA剪接机制失调之间存在密切关系。

附：英文原文

Title: DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing

Author: Yufeng Li, Junyu Xu, Yuting Lu, Hua Bian, Lin Yang, Honghong Wu, Xinwen Zhang, Beilei Zhang, Maoqian Xiong, Yafei Chang, Jie Tang, Fan Yang, Lei Zhao, Jing Li, Xin Gao, Mingfeng Xia, Minjia Tan, Jingya Li

Issue&Volume: 2021/10/05

Abstract: 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.

DOI: 10.1016/j.cmet.2021.09.008

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00427-7

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