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

doi:10.1016/j.cmet.2021.09.008

	DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing
	Li, Yufeng 1,2; Xu, Junyu 1; Lu, Yuting 1; Bian, Hua 4,5; Yang, Lin 1,2; Wu, Honghong 1,2; Zhang, Xinwen 1; Zhang, Beilei 1; Xiong, Maoqian 6; Chang, Yafei 7
刊名	CELL METABOLISM
	2021-10-05
卷号	33 期号:10 页码:2004-+
ISSN号	1550-4131
DOI	10.1016/j.cmet.2021.09.008
通讯作者	Xia, Mingfeng(dr_xiamingfeng@163.com) ; Tan, Minjia(mjtan@simm.ac.cn) ; Li, Jingya(jyli@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[92057116] ; National Natural Science Foundation of China[81673493] ; National Natural Science Foundation of China[91753203] ; National Natural Science Foundation of China[32071432] ; National Natural Science Foundation of China[81821005] ; National Science and Technology Major Project[2018ZX09711002-004/018] ; National Key R&D Program of China[2020YFE0202200] ; Shanghai Natural Science Foundation[20ZR1410200]
WOS关键词	PROTEIN-KINASE ; SYSTEM ; NASH ; STEATOHEPATITIS ; MECHANISMS ; INHIBITORS ; DISCOVERY ; APOPTOSIS ; OBESITY ; ROBUST
WOS研究方向	Cell Biology ; Endocrinology & Metabolism
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000729469700013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/299178]
专题	中国科学院上海药物研究所
通讯作者	Xia, Mingfeng; Tan, Minjia; Li, Jingya
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China 4.Fudan Univ, Zhongshan Hosp, Dept Endocrinol & Metab, Shanghai 200032, Peoples R China 5.Fudan Inst Metab Dis, Shanghai 200032, Peoples R China 6.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China 7.Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Dept Bioinformat & Biostat, Shanghai 200240, Peoples R China
推荐引用方式 GB/T 7714	Li, Yufeng,Xu, Junyu,Lu, Yuting,et al. DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing[J]. CELL METABOLISM,2021,33(10):2004-+.
APA	Li, Yufeng.,Xu, Junyu.,Lu, Yuting.,Bian, Hua.,Yang, Lin.,...&Li, Jingya.(2021).DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing.CELL METABOLISM,33(10),2004-+.
MLA	Li, Yufeng,et al."DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing".CELL METABOLISM 33.10(2021):2004-+.