Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes.
Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes.
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DOI：
10.1016/j.jlr.2023.100342
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发表时间：
2023-03
影响因子：
6.5
通讯作者：
Ruan, Xiong Z.
中科院分区：
文献类型：
--
作者：
Li, Yun;Wang, Tao;Liao, Qiumin;Luo, Xiaoting;Wang, Xing;Zeng, Shu;You, Mengyue;Chen, Yaxi;Ruan, Xiong Z.
关键词：
肝细胞内脂质蓄积是非酒精性脂肪性肝病的显著特征。富含丝氨酸/丝氨酸的剪接因子3（SRSF 3）在肝脏中高度表达，在高脂肪条件下表达降低。然而，SRSF 3在肝脏脂质代谢中的作用需要澄清。在这里，我们发现SRSF 3的丢失与脂质积累有关。我们确定SRSF 3调节脂噬作用，即通过自噬选择性降解脂滴的过程。从机制上讲，SRSF 3的缺失通过促进突触融合蛋白17（STX 17）（一种关键的自噬体SNARE蛋白）的蛋白酶体降解而损害自噬体和溶酶体的融合。我们发现，STX 17的泛素化增加和上调7缺席同源物1负责增加STX 17的翻译后修饰。综上所述，我们的数据主要表明，SRSF 3的缺失通过损害非酒精性脂肪性肝病进展中的脂肪吞噬作用来削弱脂肪酸的清除，这表明脂肪性肝病治疗的新的潜在治疗靶点。
Lipid accumulation in hepatocytes is the distinctive characteristic of nonalcoholic fatty liver disease. Serine/arginine-rich splicing factor 3 (SRSF3) is highly expressed in the liver and expression decreases in high-fat conditions. However, the role of SRSF3 in hepatic lipid metabolism needs to be clarified. Here, we showed that loss of SRSF3 was associated with lipid accumulation. We determined that SRSF3 regulated lipophagy, the process of selective degradation of lipid droplets by autophagy. Mechanistically, loss of SRSF3 impaired the fusion of the autophagosome and lysosome by promoting the proteasomal degradation of syntaxin 17 (STX17), a key autophagosomal SNARE protein. We found that ubiquitination of STX17 was increased and upregulation of seven in absentia homolog 1 was responsible for the increased posttranslational modification of STX17. Taken together, our data primarily demonstrate that loss of SRSF3 weakens the clearance of fatty acids by impairing lipophagy in the progression of nonalcoholic fatty liver disease, indicating a novel potential therapeutic target for fatty liver disease treatment.
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