Autophagosome Formation during Varicella-Zoster Virus Infection following Endoplasmic Reticulum Stress and the Unfolded Protein Response
Autophagosome Formation during Varicella-Zoster Virus Infection following Endoplasmic Reticulum Stress and the Unfolded Protein Response
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DOI：
10.1128/jvi.00281-11
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Grose, Charles
中科院分区：
文献类型：
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作者：
Carpenter, John E.;Jackson, Wallen;Grose, Charles
自噬是最近认识到的水痘-带状疱疹病毒（VZV）生命周期的组成部分。我们从随机选择的水痘和带状疱疹病例中记录了大量自噬体在皮肤囊泡（病毒粒子组装的最终位置）中形成。自噬是VZV复制周期的早期事件，通过发现被感染的囊泡细胞，VZV IE62蛋白被限制在细胞核内，证明了这一事实。接下来，我们在vzv感染的培养细胞中进行研究，以确定自噬之前是否存在内质网（ER）应激和未折叠蛋白反应（UPR）。首先，我们证明了受感染细胞中的自噬体形成与用tunicamycin（内质网应激的有效引发剂）处理细胞后的自噬体形成非常相似。其次，我们发现在感染VZV的细胞和转染了主要VZV糖蛋白复合物gE/gI的细胞中，内质网的大小都有显著的扩增。内质网增大是内质网压力的重要证据，而这种压力又会通过普遍定期审议得到缓解。为此，我们通过检测XBP1蛋白和CHOP （C/EBP同源蛋白）的可选剪接形式来记录UPR，这两种蛋白都以内质网应激依赖的方式激活其他UPR基因。由于VZV不编码自噬抑制剂，上述结果表明，自噬在VZV感染的细胞中是一种常见事件，至少部分是由过度丰富的VZV糖蛋白生物合成引起的内质网应激引起的，内质网应激导致UPR激活，试图维持细胞稳态。
Autophagy is a recently recognized component of the life cycle of varicella-zoster virus (VZV). We have documented abundant autophagosome formation in skin vesicles (final site of virion assembly) from randomly selected cases of varicella and zoster. The fact that autophagy was an early event in the VZV replication cycle was documented by finding infected vesicle cells with the VZV IE62 protein confined to the nucleus. Next, we pursued studies in VZV-infected cultured cells to define whether autophagy was preceded by endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). First, we demonstrated that autophagosome formation in infected cells closely resembled that seen after treatment of cells with tunicamycin, a potent initiator of ER stress. Second, we demonstrated a marked expansion of ER size in both VZV-infected cells and cells transfected with the predominant VZV glycoprotein complex gE/gI. An enlarged ER is critical evidence of ER stress, which in turn is relieved by the UPR. To this end, we documented the UPR by detecting the alternatively spliced form of the XBP1 protein as well as CHOP (C/EBP homologous protein), both transcriptional activators of other UPR genes in an ER stress-dependent manner. Because VZV does not encode inhibitors of autophagy, the above results suggested that autophagy was a common event in VZV-infected cells and that it was provoked at least in part by ER stress secondary to overly abundant VZV glycoprotein biosynthesis, which led to UPR activation in an attempt to maintain cellular homeostasis.