Increase of E3 ubiquitin-ligase NEDD4 expression leads to degradation of its target proteins PTEN/IGF1R during the formation of goose fatty liver
Increase of E3 ubiquitin-ligase NEDD4 expression leads to degradation of its target proteins PTEN/IGF1R during the formation of goose fatty liver
复制标题
E3泛素连接酶NEDD4表达增加导致鹅脂肪肝形成过程中其靶蛋白PTEN/IGF1R降解
DOI：
10.1093/jas/skaa270
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发表时间：
2020
影响因子：
3.3
通讯作者：
Tuoyu Geng
中科院分区：
文献类型：
--
作者：
Chunchi Yan;Minmeng Zhao;Shuo Li;Tongjun Liu;Cheng Xu;Long Liu;Daoqing Gong;Tuoyu Geng
鹅脂肪肝可能具有独特的保护机制，即使在严重脂肪变性的情况下也不显示病理损伤。虽然神经前体细胞表达的发育下调基因4（NEDD4）通过其靶蛋白参与损伤肝脏的修复和再生，但其在非酒精性脂肪性肝病中的作用仍不清楚。通过定量PCR和免疫印迹分析，我们发现NEDD4基因在鹅脂肪肝中的mRNA和蛋白表达量明显高于正常肝。第10号染色体磷酸盐和张力同源性缺失基因（PTEN）和胰岛素样生长因子1受体（IGF1R）的mRNA表达也被诱导，但其蛋白表达被抑制或有抑制的趋势。免疫共沉淀分析表明，鹅肝中NEDD4与PTEN之间存在物理联系，这与鹅脂肪肝中PTEN的泛素化一致。此外，NEDD4在鹅原代肝细胞中的过表达抑制了PTEN和IGF1R的蛋白水平，但对其mRNA表达无显著影响。因此，NEDD4在鹅脂肪肝中的表达增加，导致PTEN和IGF1R蛋白通过泛素化途径降解，提示NEDD4可能通过其靶蛋白在鹅脂肪肝发生发展过程中保护脂肪肝免受严重脂肪变性相关损伤。
Goose fatty liver may have a unique protective mechanism as it does not show a pathological injury even in the case of severe steatosis. Although neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) participates in repair and regeneration of injured liver through its target proteins, its role in nonalcoholic fatty liver disease remains unknown. Using quantitative polymerase chain reaction (PCR) and immunoblot analyses, here, we found that the messenger RNA (mRNA) and protein expressions of NEDD4 were induced in goose fatty liver compared with normal liver. The mRNA expression of the gene of phosphate and tension homology deleted on chromosome ten (PTEN) and insulin-like growth factor 1 receptor (IGF1R) was also induced in goose fatty liver; however, their protein expression was or tended to be suppressed. Moreover, the co-immunoprecipitation analysis indicated that there was a physical association between NEDD4 and PTEN in goose liver, which was consistent with the ubiquitination of PTEN in goose fatty liver. Furthermore,NEDD4overexpression in goose primary hepatocytes suppressed the PTEN and IGF1R protein levels without a significant effect on their mRNA expression. In conclusion, the increased expression of NEDD4 leads to the degradation of PTEN and IGF1R proteins through ubiquitination in goose fatty liver, suggesting that NEDD4 may protect goose fatty liver from severe steatosis-associated injury via its target proteins during the development of goose fatty liver.