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

• Published in: Nature communications Vol. 14; no. 1; pp. 7032 - 16
• Main Authors: Cui, Donghai, Wang, Zixiang, Dang, Qianli, Wang, Jing, Qin, Junchao, Song, Jianping, Zhai, Xiangyu, Zhou, Yachao, Zhao, Ling, Lu, Gang, Liu, Hongbin, Liu, Gang, Liu, Runping, Shao, Changshun, Zhang, Xiyu, Liu, Zhaojian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.11.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/51; 13/89; 14/19; 14/63; 147/28; 38/1; 38/35; 38/39; 38/61; 49/109; 49/90; 49/91; 631/337/1645; 631/443/319; 631/80/304; 631/80/39; 64/60; 82/51; 96/106; 96/31; Accumulation; Alternative splicing; Autophagy; Deletion; Fatty liver; Gene sequencing; Heat shock; Heat shock factors; Homeostasis; HSF1 protein; Humanities and Social Sciences; Immunoprecipitation; Isoforms; Lipids; Liver; Liver diseases; multidisciplinary; Proteomes; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Site selection; Steatosis; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42461-6

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. Non-alcoholic fatty liver disease affects 25% of people worldwide. Here the authors report that spliceosome component Usp39 deletion in mice leads to spontaneous steatosis and impaired autophagy through the regulation of alternative splicing.