Activation of autophagy by α-herpesviruses in myeloid cells is mediated by cytoplasmic viral DNA through a mechanism dependent on stimulator of IFN genes.
Activation of autophagy by α-herpesviruses in myeloid cells is mediated by cytoplasmic viral DNA through a mechanism dependent on stimulator of IFN genes.
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DOI：
10.4049/jimmunol.1100949
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发表时间：
2011-11-15
期刊：
影响因子：
--
通讯作者：
Paludan SR
中科院分区：
文献类型：
--
作者：
Rasmussen SB;Horan KA;Holm CK;Stranks AJ;Mettenleiter TC;Simon AK;Jensen SB;Rixon FJ;He B;Paludan SR
自噬已被确定为宿主防御病毒的一个参与者。宿主在感染过程中诱导自噬的机制是多种多样的。对于 1 型单纯疱疹病毒 (HSV-1)，dsRNA 依赖性蛋白激酶 (PKR) 对于通过真核起始因子 2α (eIF2α) 磷酸化诱导成纤维细胞自噬至关重要。 HSV-1 通过 ICP34.5 对抗自噬，ICP34.5 使 eIF2α 去磷酸化并抑制 Beclin 1。HSV-1 感染期间自噬的研究主要是在允许的细胞中进行的，但最近的工作表明在非允许的细胞中存在不依赖于 eIF2α 的自噬诱导途径。为了阐明并进一步表征非许可细胞中新的自噬诱导途径的存在，我们检查了小鼠骨髓细胞中不同的 HSV 和细胞成分在自噬中的作用。我们证明HSV-1诱导的自噬与eIF2α的磷酸化无关，不依赖于功能性PKR，并且不被ICP34.5拮抗。自噬的激活独立于病毒基因表达，但需要病毒进入。重要的是，我们发现病毒粒子中基因组 DNA 的存在对于诱导自噬至关重要，相反，HSV 衍生 DNA 的转染诱导了 LC3 II 的形成，这是自噬的标志物。这是通过依赖于 STING 的机制发生的，STING 是 IFN 对细胞内 DNA 做出反应的重要组成部分。最后，我们观察到 HSV-1 感染 DC 后，HSV-1 DNA 存在于缺乏衣壳物质的细胞质中。因此，我们的数据表明，HSV-1 基因组 DNA 以 STING 依赖性方式在非许可细胞中诱导自噬。
Autophagy has been established as a player in host defense against viruses. The mechanisms by which the host induces autophagy during infection are diverse. In the case of herpes simplex virus type 1 (HSV-1), dsRNA dependent protein kinase (PKR) is essential for induction of autophagy in fibroblasts through phosphorylation of eukaryotic initiation factor 2α (eIF2α). HSV-1 counteracts autophagy via ICP34.5, which dephosphorylates eIF2α and inhibits Beclin 1. Investigation of autophagy during HSV-1 infection has largely been conducted in permissive cells, but recent work suggests the existence of an eIF2α-independent autophagy-inducing pathway in non-permissive cells. To clarify and further characterize the existence of a novel autophagy-inducing pathway in non-permissive cells, we examined different HSV and cellular components in murine myeloid cells for their role in autophagy. We demonstrate that HSV-1-induced autophagy does not correlate with phosphorylation of eIF2α, is independent of functional PKR, and is not antagonized by ICP34.5. Autophagy was activated independent of viral gene expression but required viral entry. Importantly, we found that the presence of genomic DNA in the virion was essential for induction of autophagy and, conversely, that transfection of HSV-derived DNA induced LC3 II formation, a marker of autophagy. This occurred through a mechanism dependent on STING, an essential component for the IFN response to intracellular DNA. Finally we observed that HSV-1 DNA was present in the cytosol devoid of capsid material following HSV-1 infection of DCs. Thus, our data suggest that HSV-1 genomic DNA induces autophagy in non-permissive cells in a STING dependent manner.
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