Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy
Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy
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DOI：
10.1096/fj.201500119
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发表时间：
2016-07-01
期刊：
影响因子：
4.8
通讯作者：
Ye, Ji-Ming
中科院分区：
文献类型：
--
作者：
Wang, Hao;Sun, Ruo-Qiong;Ye, Ji-Ming
内质网（ER）内未折叠蛋白质的积累会导致内质网应激以及未折叠蛋白反应（UPR）的激活。这种反应可触发内质网相关降解和自噬，从而清除未折叠蛋白质并恢复蛋白质稳态。近来，已明确泛素化在自噬的调控中起重要作用。在本研究中，我们探讨了E3泛素连接酶神经前体细胞表达的发育性下调蛋白4 - 2（Nedd4 - 2）如何与内质网应激和自噬相互作用。在小鼠中，我们发现Nedd4 - 2表达增加，这与UPR和自噬的激活同时发生，是由诱导肝脏内质网应激的长期高果糖和高脂肪饮食所引起。内质网应激的药物诱导也导致培养细胞中Nedd4 - 2表达增加，这与UPR和自噬激活同时发生。肌醇需求酶1的抑制显著抑制了Nedd4 - 2的表达。此外，体内Nedd4 - 2表达增加与肌醇需求酶1的激活以及X - 盒结合蛋白1剪接形式的表达增加密切相关。再者，在培养细胞中敲低Nedd4 - 2抑制了基础自噬和内质网应激诱导的自噬，而Nedd4 - 2的过表达则诱导自噬。综上所述，我们的研究结果提供了证据，表明Nedd4 - 2通过X - 盒结合蛋白1的剪接形式响应内质网应激而上调，并且这在诱导适当的自噬反应中很重要。
The accumulation of unfolded proteins within the endoplasmic reticulum (ER) causes ER stress and activation of unfolded protein response (UPR). This response can trigger ER-associated degradation and autophagy, which clear unfolded proteins and restore protein homeostasis. Recently, it has become clear that ubiquitination plays an important role in the regulation of autophagy. In the present study, we investigated how the E3 ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 (Nedd4-2) interacts with ER stress and autophagy. In mice, we found that an increase in the expression of Nedd4-2, which was concomitant with the activation of the UPR and autophagy, was caused by a prolonged high-fructose and high-fat diet that induces ER stress in the liver. Pharmacologic induction of ER stress also led to an increase in Nedd4-2 expression in cultured cells, which was coincident with UPR and autophagy activation. The inhibition of inositol-requiring enzyme 1 significantly suppressed Nedd4-2 expression. Moreover, increased Nedd4-2 expression in vivo was closely associated with the activation of inositol-requiring enzyme1 and increased expression of the spliced form of X-box binding protein 1. Furthermore, knockdown of Nedd4-2 in cultured cells suppressed both basal autophagy and ER stress-induced autophagy, whereas overexpression of Nedd4-2-induced autophagy. Taken together, our findings provide evidence that Nedd4-2 is up-regulated in response to ER stress by the spliced form of X-box binding protein 1 and that this is important in the induction of an appropriate autophagic response.