Schock Suruchi N, Chandra Neha V, Sun Yuefang, Irie Takashi, Kitagawa Yoshinori, Gotoh Bin, Coscoy Laurent, Winoto Astar
Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA.
Department of Virology, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Cell Death Differ. 2017 Apr;24(4):615-625. doi: 10.1038/cdd.2016.153. Epub 2017 Jan 6.
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.
坏死性凋亡是一种坏死性细胞死亡形式，需要含死亡结构域的激酶RIP1及其家族成员RIP3的活性。当死亡受体衔接分子FADD或半胱天冬酶-8缺陷的细胞中RIP1去泛素化并与RIP3形成复合物时，就会发生坏死性凋亡。坏死性凋亡可能在病毒感染期间的宿主防御中发挥作用，因为痘苗病毒等病毒可诱导坏死性凋亡，而鼠巨细胞病毒编码一种坏死性凋亡的病毒抑制剂。为了了解病毒与坏死性凋亡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，所测试的两种病毒，仙台病毒（SeV）和鼠γ疱疹病毒68（MHV68），能够在纤维肉瘤L929细胞系中诱导显著的坏死性凋亡。我们表明，MHV68诱导的细胞死亡通过胞质STING传感器途径以TNF依赖的方式发生。相比之下，SeV诱导的死亡大多独立于TNF。敲低RNA传感分子RIG-I或RIP1去泛素化蛋白CYLD，但不敲低STING，可使细胞免受SeV诱导的坏死性凋亡。伴随着坏死性凋亡，我们还发现，缺乏病毒蛋白Y1和Y2的野生型而非突变型SeV会导致RIP1的非泛素化形式。单独表达Y1或Y2可抑制RIP1泛素化，但CYLD对此过程是可有可无的。相反，我们发现Y1和Y2可抑制cIAP1介导的RIP1泛素化。有趣的是，我们还发现B6 RIP3小鼠感染SeV会导致肺部炎症增加和SeV特异性T细胞升高。总的来说，这些数据确定了可引发坏死性凋亡的病毒和途径，并突出了病原体识别受体与细胞死亡诱导之间的动态相互作用。
