Spliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy

Donghai Cui, Zixiang Wang, Qianli Dang, Jing Wang, Junchao Qin, Jianping Song, Xiangyu Zhai, Yachao Zhou, Ling Zhao, Gang Lu, Hongbin Liu, Gang Liu, Runping Liu, Changshun Shao (), Xiyu Zhang () and Zhaojian Liu ()
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Donghai Cui: Shandong University
Zixiang Wang: Shandong University
Qianli Dang: Shandong University
Jing Wang: Shandong University
Junchao Qin: Shandong University
Jianping Song: Shandong University
Xiangyu Zhai: Shandong University
Yachao Zhou: Shandong University
Ling Zhao: Shandong University
Gang Lu: The Chinese University of Hong Kong
Hongbin Liu: Shandong University
Gang Liu: The Second Hospital of Shandong University
Runping Liu: Beijing University of Chinese Medicine
Changshun Shao: Soochow University
Xiyu Zhang: Shandong University
Zhaojian Liu: Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Regulation of alternative splicing (AS) enables a single transcript to yield multiple isoforms that increase transcriptome and proteome diversity. Here, we report that spliceosome component Usp39 plays a role in the regulation of hepatocyte lipid homeostasis. We demonstrate that Usp39 expression is downregulated in hepatic tissues of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) subjects. Hepatocyte-specific Usp39 deletion in mice leads to increased lipid accumulation, spontaneous steatosis and impaired autophagy. Combined analysis of RNA immunoprecipitation (RIP-seq) and bulk RNA sequencing (RNA-seq) data reveals that Usp39 regulates AS of several autophagy-related genes. In particular, deletion of Usp39 results in alternative 5’ splice site selection of exon 6 in Heat shock transcription factor 1 (Hsf1) and consequently its reduced expression. Importantly, overexpression of Hsf1 could attenuate lipid accumulation caused by Usp39 deficiency. Taken together, our findings indicate that Usp39-mediated AS is required for sustaining autophagy and lipid homeostasis in the liver.

Date: 2023
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DOI: 10.1038/s41467-023-42461-6

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