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RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway

2014; Nature Portfolio; Volume: 15; Issue: 12 Linguagem: Inglês

10.1038/ni.3015

1529-2916

Xiaqiong Wang, Wei Jiang, Yiqing Yan, Tao Gong, Jiahuai Han, Zhigang Tian, Rongbin Zhou,

Kawasaki Disease and Coronary Complications

The mechanisms by which viruses activate the NLRP3 inflammasome remain unclear. Zhou and colleagues show that RNA viruses initiate a RIP1-RIP3 complex that drives mitochondrial damage and activation of the NLRP3 inflammasome independently of necrosis. 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.