Degradation of splicing factor SRSF3 contributes to progressive liver disease.

The Journal of Clinical Investigation
Deepak KumarNicholas J G Webster

Abstract

Serine rich splicing factor 3 (SRSF3) plays a critical role in liver function and its loss promotes chronic liver damage and regeneration. As a consequence, genetic deletion of SRSF3 in hepatocytes caused progressive liver disease and ultimately led to hepatocellular carcinoma. Here we show that SRSF3 is decreased in human liver samples with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or cirrhosis that was associated with alterations in RNA splicing of known SRSF3 target genes. Hepatic SRSF3 expression was similarly decreased and RNA splicing dysregulated in mouse models of NAFLD and NASH. We showed that palmitic acid-induced oxidative stress caused conjugation of the ubiquitin like NEDD8 protein to SRSF3 and proteasome mediated degradation. SRSF3 was selectively neddylated at lysine11 and mutation of this residue (SRSF3-K11R) was sufficient to prevent both SRSF3 degradation and alterations in RNA splicing. Finally prevention of SRSF3 degradation in vivo partially protected mice from hepatic steatosis, fibrosis and inflammation. These results highlight a neddylation-dependent mechanism regulating gene expression in the liver that is disrupted in early metabolic liver disease and may contribu...Continue Reading

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Citations

Sep 23, 2020·International Journal of Molecular Sciences·Jonas WeißeTony Gutschner
Oct 8, 2020·The FEBS Journal·Tao Zou, Jiyan Zhang
Jan 5, 2021·Frontiers in Physiology·Jie LiHuabo Su
Feb 9, 2021·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Rebecca E Wagner, Michaela Frye
Nov 17, 2020·Frontiers in Medicine·Jiping YaoMin Zheng
Mar 16, 2021·Frontiers in Endocrinology·Panyisha WuNicholas J G Webster
Mar 19, 2021·Cell & Bioscience·Qiyin ZhouYi Sun
Apr 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Audrey-Ann DumontMannix Auger-Messier
May 23, 2021·Biochimie·Takahito NakuraShin-Ichiro Takahashi
Jun 15, 2021·Pathology, Research and Practice·Han Wang, Yanxia Jiang
Jun 22, 2021·Molecular Metabolism·Marina Serrano-MaciáMaría Luz Martínez-Chantar
Oct 3, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Si-Wei XiaShi-Zhong Zheng

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Datasets Mentioned

BETA
GSE133398
GSE133400

Methods Mentioned

BETA
neddylation
PCR
reverse transcription PCR
RNAseq
ubiquitination
transfection
immunoprecipitation assay
proteomic profiling

Software Mentioned

Prism Graph Pad
Aperio ImageScope
ImageScope
JUM
MAJIQ
Leica

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