Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway
Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway
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DOI：
10.1038/cdd.2016.153
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发表时间：
2017-04-01
影响因子：
12.4
通讯作者：
Winoto, Astar
中科院分区：
文献类型：
--
作者：
Schock, Suruchi N.;Chandra, Neha V.;Winoto, Astar
坏死性下垂是一种坏死性细胞死亡，需要含有死亡结构域的激酶RIP1及其家族成员RIP3的活性。当RIP1在缺乏死亡受体适配分子FADD或caspase-8的细胞中被去泛素化以与RIP3形成复合体时，就会发生坏死性下垂。在病毒感染期间，坏死性下垂可能在宿主防御中发挥作用，因为像牛痘这样的病毒可以诱导坏死性下垂，而小鼠巨细胞病毒编码一种坏死性下垂的病毒抑制物。为了了解病毒和坏死性下垂之间的相互作用有多普遍，我们调查了七种不同的病毒。我们发现，其中两种病毒，仙台病毒(SeV)和小鼠伽马疱疹病毒-68(MHV68)，能够诱导纤维肉瘤L929细胞株发生显著的坏死性下垂。我们发现，MHV68诱导的细胞死亡是通过胞质刺痛感受器通路以肿瘤坏死因子依赖的方式发生的。相反，SeV诱导的死亡在很大程度上不依赖于肿瘤坏死因子。敲除RNA传感分子RIG-I或RIP1去泛素蛋白，CyLD，而不是STING，将细胞从SeV诱导的坏死性下垂中拯救出来。伴随着坏死性下垂，我们还发现缺乏病毒蛋白Y1和Y2的野生型而不是突变型SeV导致了RIP1的非泛素化形式。单独表达Y1或Y2可以抑制RIP1泛素化，但CyLD对这一过程是必不可少的。相反，我们发现Y1和Y2可以抑制cIAP1介导的RIP1泛素化。有趣的是，我们还发现，B6RIP3(-/-)小鼠感染SeV会导致肺部炎症增加，SeV特异性T细胞增加。总的来说，这些数据确定了可以引发坏死性下垂的病毒和途径，并突出了病原体识别受体和细胞死亡诱导之间的动态相互作用。
Necroptosis is a form of necrotic cell death that requires the activity of the death domain-containing kinase RIP1 and its family member RIP3. Necroptosis occurs when RIP1 is deubiquitinated to form a complex with RIP3 in cells deficient in the death receptor adapter molecule FADD or caspase-8. Necroptosis may play a role in host defense during viral infection as viruses like vaccinia can induce necroptosis while murine cytomegalovirus encodes a viral inhibitor of necroptosis. To see how general the interplay between viruses and necroptosis is, we surveyed seven different viruses. We found that two of the viruses tested, Sendai virus (SeV) and murine gammaherpesvirus-68 (MHV68), are capable of inducing dramatic necroptosis in the fibrosarcoma L929 cell line. We show that MHV68-induced cell death occurs through the cytosolic STING sensor pathway in a TNF-dependent manner. In contrast, SeV-induced death is mostly independent of TNF. Knockdown of the RNA sensing molecule RIG-I or the RIP1 deubiquitin protein, CYLD, but not STING, rescued cells from SeV-induced necroptosis. Accompanying necroptosis, we also find that wild type but not mutant SeV lacking the viral proteins Y1 and Y2 result in the non-ubiquitinated form of RIP1. Expression of Y1 or Y2 alone can suppress RIP1 ubiquitination but CYLD is dispensable for this process. Instead, we found that Y1 and Y2 can inhibit cIAP1-mediated RIP1 ubiquitination. Interestingly, we also found that SeV infection of B6 RIP3(-/-) mice results in increased inflammation in the lung and elevated SeV-specific T cells. Collectively, these data identify viruses and pathways that can trigger necroptosis and highlight the dynamic interplay between pathogen-recognition receptors and cell death induction.