RNA 病毒通过 RIP1-RIP3-DRP1 信号通路促进 NLRP3 炎性小体的激活。
RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway.
机构信息
Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Biology, Xiamen University, Xiamen, Fujian, China.
出版信息
Nat Immunol. 2014 Dec;15(12):1126-33. doi: 10.1038/ni.3015. Epub 2014 Oct 19.
The NLRP3 inflammasome functions as a crucial component of the innate immune system in recognizing viral infection, but the mechanism by which viruses activate this inflammasome remains unclear. Here we found that inhibition of the serine-threonine kinases RIP1 (RIPK1) or RIP3 (RIPK3) suppressed RNA virus-induced activation of the NLRP3 inflammasome. Infection with an RNA virus initiated assembly of the RIP1-RIP3 complex, which promoted activation of the GTPase DRP1 and its translocation to mitochondria to drive mitochondrial damage and activation of the NLRP3 inflammasome. Notably, the RIP1-RIP3 complex drove the NLRP3 inflammasome independently of MLKL, an essential downstream effector of RIP1-RIP3-dependent necrosis. Together our results reveal a specific role for the RIP1-RIP3-DRP1 pathway in RNA virus-induced activation of the NLRP3 inflammasome and establish a direct link between inflammation and cell-death signaling pathways.
NLRP3 炎性小体作为先天免疫系统识别病毒感染的关键组成部分，但其激活机制仍不清楚。在这里，我们发现抑制丝氨酸-苏氨酸激酶 RIP1（RIPK1）或 RIP3（RIPK3）可抑制 RNA 病毒诱导的 NLRP3 炎性小体的激活。RNA 病毒感染引发 RIP1-RIP3 复合物的组装，从而促进 GTPase DRP1 的激活及其向线粒体的易位，以驱动线粒体损伤和 NLRP3 炎性小体的激活。值得注意的是，RIP1-RIP3 复合物独立于 RIP1-RIP3 依赖性坏死的必需下游效应子 MLKL 驱动 NLRP3 炎性小体的激活。我们的研究结果揭示了 RIP1-RIP3-DRP1 途径在 RNA 病毒诱导的 NLRP3 炎性小体激活中的特定作用，并在炎症和细胞死亡信号通路之间建立了直接联系。
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