Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway
Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway
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DOI：
10.1128/jvi.76.15.7453-7459.2002
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发表时间：
2002-08-01
影响因子：
5.4
通讯作者：
Siddiqui, A
中科院分区：
文献类型：
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作者：
Tardif, KD;Mori, K;Siddiqui, A
丙型肝炎病毒(HCV)从与内质网(ER)膜相关的核糖核蛋白(RNP)复合体复制。这里显示了丙型肝炎病毒亚基因组复制子的复制活性，以诱导内质网压力。作为对这种压力的响应，表达丙型肝炎病毒复制子的细胞诱导未折叠蛋白反应(UPR)，这是一种内质网到胞核的信号通路。UPR是由跨膜蛋白ATF6的蛋白水解性切割而启动的。由此产生的ATF6细胞质蛋白片段在细胞核中起到转录因子的作用，并激活内质网应激反应所需的选择性基因。ATF6激活导致GRP78转录水平增加，GRP78是一种内质网伴侣蛋白。然而，GRP78蛋白的总体水平有所下降。虽然已知内质网应激也会影响翻译衰减，但表达丙型肝炎病毒复制子的细胞对真核细胞起始因子2的α亚基的磷酸化水平较低。有趣的是，在表达丙型肝炎病毒复制子的细胞中，由丙型肝炎病毒5‘非编码区和GRP78引导的帽非依赖性内部核糖体进入位点介导的翻译被激活。这些研究为深入了解丙型肝炎病毒复制对细胞内事件的影响以及潜在的肝脏发病机制提供了线索。
Hepatitis C virus (HCV) replicates from a ribonucleoprotein (RNP) complex that is associated with the endoplasmic reticulum (ER) membrane. The replication activities of the HCV subgenomic replicon are shown here to induce ER stress. In response to this stress, cells expressing HCV replicons induce the unfolded protein response (UPR), an ER-to-nucleus intracellular signaling pathway. The UPR is initiated by the proteolytic cleavage of a transmembrane protein, ATF6. The resulting cytoplasmic protein fragment of ATF6 functions as a transcription factor in the nucleus and activates selective genes required for an ER stress response. ATF6 activation leads to increased transcriptional levels of GRP78, an ER luminal chaperone protein. However, the overall level of GRP78 protein is decreased. While ER stress is also known to affect translational attenuation, cells expressing HCV replicons have lower levels of phosphorylation of the alpha subunit of eukaryotic initiation factor 2. Interestingly, cap-independent internal ribosome entry site-mediated translation directed by the 5' noncoding region of HCV and GRP78 is activated in cells expressing HCV replicons. These studies provide insight into the effects of HCV replication on intracellular events and the mechanisms underlying liver pathogenesis.