Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis.
Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis.
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通过双链RNA依赖性RLR受体介导的坏死性凋亡激活先天抗病毒免疫反应
DOI：
10.1038/srep22550
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发表时间：
2016-03-03
影响因子：
4.6
通讯作者：
Yang JH
中科院分区：
文献类型：
--
作者：
Wang W;Wang WH;Azadzoi KM;Su N;Dai P;Sun J;Wang Q;Liang P;Zhang W;Lei X;Yan Z;Yang JH
病毒在宿主细胞中诱导双链RNA（dsRNA）。哺乳动物系统已经开发了dsRNA依赖性识别受体，如TLR，其将dsRNA的长片段识别为PAMP，以激活干扰素介导的抗病毒途径和严重感染中的细胞凋亡。在这里，我们报告了一种有效的抗病毒免疫反应，通过dsRNA依赖性RLR受体介导的坏死性凋亡对感染的不同类别的病毒。我们证明了在嵌合RLR受体dsCARE存在下，病毒感染的A549细胞被有效地杀死。它可测量地抑制干扰素抗病毒途径，但促进IL-1β的产生。通过形态学评估、磷脂酰丝氨酸暴露、半胱天冬酶裂解和化学抑制进行的典型细胞死亡分析排除了细胞凋亡的参与，并一致表明RLR受体介导的坏死性凋亡是感染细胞死亡的潜在机制。RIP 1-RIP 3坏死体的形成、MLKL蛋白的募集和组织蛋白酶D的激活增强了坏死性凋亡途径。RIP 1和RIP 3的贡献作用通过基因敲低得到证实。此外，坏死性凋亡抑制剂necrostatin-1而非泛半胱天冬酶抑制剂zVAD阻碍dsCARE依赖性感染细胞死亡。我们的数据提供了令人信服的证据表明，嵌合RLR受体将感染细胞的常见干扰素抗病毒反应转变为坏死性凋亡，并导致病毒感染细胞的快速死亡。这种机制可以作为一种有效的抗病毒策略。
Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1β production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy.