Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response
Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response
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DOI：
10.1096/fj.04-3455fje
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发表时间：
2005-07-01
期刊：
影响因子：
4.8
通讯作者：
Egan, PA
中科院分区：
文献类型：
--
作者：
Chan, SW;Egan, PA
未折叠蛋白反应（Unfolded protein response，UPR）是一种细胞适应性反应，其功能是减少由内质网（endoplasmic reticulum，ER）中的错误折叠蛋白引起的应激。UPR可以在生理或病理条件下诱导，并负责许多人类疾病的发病机制。丙型肝炎病毒（HCV）是一种单链、正义RNA病毒，可引起慢性疾病。其基因组编码两种包膜蛋白E1和E2，其在ER中成熟以形成非共价结合的天然复合物和二硫键聚集体，并且先前已显示诱导分子伴侣免疫球蛋白重链结合蛋白的表达。在这项研究中，我们表明，HCV包膜蛋白的表达调节另一个应激指标CCAAT/增强子结合蛋白同源蛋白（CHOP）。在CHOP启动子中的ER-应激元件和转录激活因子4元件被HCV包膜蛋白表达激活到相似的程度。使用缺乏ER应激激酶RNA活化蛋白激酶样ER驻留激酶（PERK）的小鼠胚胎成纤维细胞，我们发现PERK是激活CHOP启动子所必需和充分的。HCV E1和/或E2的表达还诱导X-box结合蛋白1的剪接和未折叠蛋白反应元件的反式激活，导致推测HCV E1和E2不仅调节UPR，而且还调节ER相关的降解。
Unfolded protein response (UPR) is a cellular adaptive response that functions to reduce stress caused by malfolded proteins in the endoplasmic reticulum ( ER). UPR can be induced under physiological or pathological conditions and is responsible for the pathogenesis of many human diseases. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus causing chronic diseases. Its genome encodes two envelope proteins E1 and E2, which mature in the ER to form a noncovalently bound, native complex and disulfide aggregates and have previously been shown to induce expression of the molecular chaperone immunoglobulin heavy chain binding protein. In this study, we show that HCV envelope protein expression regulates another stress indicator CCAAT/enhancer-binding protein-homologous protein (CHOP). The ER-stress element and the activating transcription factor 4 element in the CHOP promoter were activated to a similar extent by HCV envelope protein expression. Using mouse embryonic fibroblasts deficient in the ER stress kinase RNA-activated protein kinase-like ER-resident kinase (PERK), we showed that PERK was necessary and sufficient for activating the CHOP promoter. Expression of HCV E1 and/or E2 also induced splicing of X-box binding protein 1 and transactivation of the unfolded protein response element, leading to the speculation that HCV E1 and E2 not only regulate the UPR but also ER-associated degradation.