Degradation of splicing factor SRSF3 contributes to progressive liver disease
Degradation of splicing factor SRSF3 contributes to progressive liver disease
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DOI：
10.1172/jci127374
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发表时间：
2019-10-01
影响因子：
15.9
通讯作者：
Webstert, Nicholas J. G.
中科院分区：
文献类型：
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作者：
Kumar, Deepak;Das, Manasi;Webstert, Nicholas J. G.
富含丝氨酸的剪接因子 3 (SRSF3) 在肝功能中发挥着关键作用，其缺失会促进慢性肝损伤和再生。因此，肝细胞中 SRSF3 的基因缺失导致进行性肝病，并最终导致肝细胞癌。在这里，我们发现，在患有非酒精性脂肪性肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）或肝硬化的人类肝脏样本中，SRSF3 减少，这与已知 SRSF3 靶基因的 RNA 剪接的改变有关。在 NAFLD 和 NASH 小鼠模型中，肝脏 SRSF3 表达同样降低，RNA 剪接失调。我们发现，棕榈酸诱导的氧化应激导致泛素样 NEDD8 蛋白与 SRSF3 结合，并引起蛋白酶体介导的降解。 SRSF3 在赖氨酸 11 处被选择性地 neddylated，并且该残基 (SRSF3-K11R) 的突变足以防止 SRSF3 降解和 RNA 剪接的改变。最后，防止 SRSF3 体内降解可部分保护小鼠免受肝脏脂肪变性、纤维化和炎症的影响。这些结果强调了肝脏中调节基因表达的依赖于neddylation的机制，该机制在早期代谢性肝病中被破坏，并可能导致NASH、肝硬化和最终肝细胞癌的进展。
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 nonalcoholic fatty liver disease (NAFLD), nonalcoholic 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 lysine 11 and mutation of this residue (SRSF3-K11R) was sufficient to prevent both SRSF3 degradation and alterations in RNA splicing. Lastly, 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 contribute to the progression to NASH, cirrhosis, and ultimately hepatocellular carcinoma.