DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing
DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing
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DRAK2通过SRSF6相关RNA选择性剪接加重非酒精性脂肪肝疾病进展
DOI：
10.1016/j.cmet.2021.09.008
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发表时间：
2021-10-05
期刊：
影响因子：
29
通讯作者：
Li, Jingya
中科院分区：
文献类型：
--
作者：
Li, Yufeng;Xu, Junyu;Li, Jingya
非酒精性脂肪性肝炎（NASH）是一种晚期非酒精性脂肪性肝病（NAFLD），具有严重的后果，目前缺乏经批准的药物治疗方法。近年来的研究表明，NAFLD的发病机制与RNA剪接机制的失调密切相关。在这里，我们发现死亡相关蛋白激酶相关的凋亡诱导激酶-2 （DRAK2）在NAFLD/NASH患者和NAFLD/NASH饮食小鼠的肝脏中均显着上调。肝脏缺失DRAK2可抑制肝脂肪变性向NASH的进展。磷酸化蛋白组和转录组的综合分析表明，DRAK2在RNA剪接中起着至关重要的作用，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结合可抑制SRSF6激酶SRPK1的磷酸化，并调节线粒体功能相关基因的选择性剪接。总之，我们的研究结果揭示了DRAK2在NAFLD/NASH中不可或缺的作用，并为该疾病提供了潜在的治疗靶点。
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.