DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing - PubMed (original) (raw)

. 2021 Oct 5;33(10):2004-2020.e9.

doi: 10.1016/j.cmet.2021.09.008.

Junyu Xu 2, Yuting Lu 2, Hua Bian 3, Lin Yang 1, Honghong Wu 1, Xinwen Zhang 2, Beilei Zhang 2, Maoqian Xiong 4, Yafei Chang 5, Jie Tang 4, Fan Yang 4, Lei Zhao 2, Jing Li 5, Xin Gao 3, Mingfeng Xia 6, Minjia Tan 7, Jingya Li 8

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

Yufeng Li et al. Cell Metab. 2021.

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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.

Keywords: Drak2; RNA alternative splicing; hepatic steatosis; mitochondrial function; mtDNA; nonalcoholic fatty liver disease; serine/arginine-rich splicing factor (SRSF).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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Declaration of interests The authors declare no competing interests.

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