Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways
Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways
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DOI：
10.1073/pnas.1616829114
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发表时间：
2017-03-28
影响因子：
11.1
通讯作者：
Mocarski, Edward S.
中科院分区：
文献类型：
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作者：
Daley-Bauer, Lisa P.;Roback, Linda;Mocarski, Edward S.
caspase-8和受体相互作用蛋白（RIP）激酶RIPK 3（RIPK 3）驱动外源性凋亡和坏死性凋亡之间的复杂相互作用尚未完全了解。鼠巨细胞病毒在感染细胞中触发凋亡和坏死性凋亡;然而，编码的半胱天冬酶-8活性抑制剂（M36）和RIP 3信号传导抑制剂（M45）抑制这些抗病毒反应。在这里，我们报告说，这种病毒激活caspase-8在巨噬细胞引发细胞凋亡，引起继发性坏死性凋亡。双突变Delta M36/M45 mutRHIM病毒感染揭示了一种信号传导模式，其中caspase-8激活caspase-3以驱动细胞凋亡，随后RIP 3依赖性激活混合谱系激酶结构域样（MLKL），导致坏死性凋亡。这种组合的细胞死亡信号传导是高度炎性的，大于由Delta M36诱导的细胞凋亡或由M45 mutRHIM病毒诱导的坏死性凋亡。在双突变病毒感染期间，巨噬细胞产生的IL-6显著增加，并与宿主中更快的抗病毒反应相关。M36和M45共同靶向caspase-8和RIP 3通路，以抑制这种促炎性细胞死亡。这项研究揭示了抗病毒程序性细胞死亡途径对炎症的影响，表明caspase-8的激活可能与巨噬细胞的坏死性凋亡密切相关，并修改了目前对M36和M45在阻断凋亡和坏死性细胞死亡反应中的独立和协同功能的理解。
The complex interplay between caspase-8 and receptor-interacting protein (RIP) kinase RIP 3 (RIPK3) driving extrinsic apoptosis and necroptosis is not fully understood. Murine cytomegalovirus triggers both apoptosis and necroptosis in infected cells; however, encoded inhibitors of caspase-8 activity (M36) and RIP3 signaling (M45) suppress these antiviral responses. Here, we report that this virus activates caspase-8 in macrophages to trigger apoptosis that gives rise to secondary necroptosis. Infection with double-mutant Delta M36/M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3-dependent activation of mixed lineage kinase domain-like (MLKL) leading to necroptosis. This combined cell death signaling is highly inflammatory, greater than either apoptosis induced by Delta M36 or necroptosis induced by M45mutRHIM virus. IL-6 production by macrophages is dramatically increased during double-mutant virus infection and correlates with faster antiviral responses in the host. Collaboratively, M36 and M45 target caspase-8 and RIP3 pathways together to suppress this proinflammatory cell death. This study reveals the effect of antiviral programmed cell death pathways on inflammation, shows that caspase-8 activation may go hand-inhand with necroptosis in macrophages, and revises current understanding of independent and collaborative functions of M36 and M45 in blocking apoptotic and necroptotic cell death responses.