The Ribonucleotide Reductase R1 Subunits of Herpes Simplex Virus 1 and 2 Protect Cells against Poly(I • C)-Induced Apoptosis
The Ribonucleotide Reductase R1 Subunits of Herpes Simplex Virus 1 and 2 Protect Cells against Poly(I • C)-Induced Apoptosis
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DOI：
10.1128/jvi.00362-11
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Langelier, Yves
中科院分区：
文献类型：
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作者：
Dufour, Florent;Bertrand, Luc;Langelier, Yves
我们最近提供的证据表明，单纯疱疹病毒 1 型和 2 型（HSV-1 和 -2）的核糖核苷酸还原酶 R1 亚基通过与 caspase 8 相互作用，保护细胞免受肿瘤坏死因子 α 和 Fas 配体诱导的细胞凋亡。双链 RNA (dsRNA) 是一种已知可引发先天抗病毒反应的病毒中间体。 Poly(I center dot C) 是病毒 dsRNA 的合成类似物，可快速触发 HeLa 细胞中的 caspase 8 激活和细胞凋亡。在这里，我们报道了 HSV-1 和 HSV-2 感染后的 HeLa 细胞迅速受到保护，免于细胞外聚（I 中心点 C）联合放线菌酮或转染聚（I 中心点 C）引起的细胞凋亡。感染HSV-1 R1缺失突变体ICP6 Delta的细胞被聚（I中心点C）杀死，表明HSV-1 R1在聚（I中心点C）的抗凋亡反应中发挥关键作用。单独表达的 HSV R1 通过聚（I 中心点 C）抵消 caspase 8 激活。除了与 caspase 8 结合外，HSV R1 在 HSV 感染期间单独表达或与其他病毒蛋白一起表达时，还与受体相互作用蛋白 1 (RIP1) 发生组成型相互作用。 R1(1-834)-绿色荧光蛋白 (GFP) 是一种缺乏抗凋亡活性的 HSV-2 R1 缺失突变蛋白，不与 caspase 8 和 RIP1 相互作用，表明这些相互作用是针对聚 (I 中心点 C) 的保护所必需的。 HSV-2 R1 抑制含有 Toll/interleukin-1 受体结构域的接头诱导型 β 干扰素 (IFN-β) (TRIF) 和 RIP1 之间的相互作用，这种相互作用对于细胞外聚（I 中心点 C）加放线菌酮或 TRIF 过表达触发的细胞凋亡至关重要。 TRIF 沉默减少了模拟和 ICP6 Delta 感染细胞中聚（I 中心点 C）触发的 caspase 8 激活，证实 TRIF 参与聚（I 中心点 C）诱导的细胞凋亡。因此，通过与 caspase 8 和 RIP1 相互作用，HSV R1 损害了 dsRNA 引发的细胞凋亡宿主防御机制。
We recently provided evidence that the ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 (HSV-1 and -2) protect cells against tumor necrosis factor alpha-and Fas ligand-induced apoptosis by interacting with caspase 8. Double-stranded RNA (dsRNA) is a viral intermediate known to initiate innate antiviral responses. Poly(I center dot C), a synthetic analogue of viral dsRNA, rapidly triggers caspase 8 activation and apoptosis in HeLa cells. Here, we report that HeLa cells after HSV-1 and HSV-2 infection were quickly protected from apoptosis caused by either extracellular poly(I center dot C) combined with cycloheximide or transfected poly(I center dot C). Cells infected with the HSV-1 R1 deletion mutant ICP6 Delta were killed by poly(I center dot C), indicating that HSV-1 R1 plays a key role in antiapoptotic responses to poly(I center dot C). Individually expressed HSV R1s counteracted caspase 8 activation by poly(I center dot C). In addition to their binding to caspase 8, HSV R1s also interacted constitutively with receptor-interacting protein 1 (RIP1) when expressed either individually or with other viral proteins during HSV infection. R1(1-834)-green fluorescent protein (GFP), an HSV-2 R1 deletion mutant protein devoid of antiapoptotic activity, did not interact with caspase 8 and RIP1, suggesting that these interactions are required for protection against poly(I center dot C). HSV-2 R1 inhibited the interaction between the Toll/interleukin-1 receptor domain-containing adaptor-inducing beta interferon (IFN-beta) (TRIF) and RIP1, an interaction that is essential for apoptosis triggered by extracellular poly(I center dot C) plus cycloheximide or TRIF overexpression. TRIF silencing reduced poly(I center dot C)-triggered caspase 8 activation in mock-and ICP6 Delta-infected cells, confirming that TRIF is involved in poly(I center dot C)-induced apoptosis. Thus, by interacting with caspase 8 and RIP1, HSV R1s impair the apoptotic host defense mechanism prompted by dsRNA.