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

• Published in: Nature immunology Vol. 15; no. 12; pp. 1126 - 1133
• Main Authors: Wang, Xiaqiong, Jiang, Wei, Yan, Yiqing, Gong, Tao, Han, Jiahuai, Tian, Zhigang, Zhou, Rongbin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2014; Nature Publishing Group
• Subjects: 13/109; 13/21; 13/89; 14/1; 14/19; 631/250/256/2177; Animals; Biomedicine; Carrier Proteins - immunology; Cell death; Cell Line; Dynamins - immunology; Enzyme-Linked Immunosorbent Assay; Genetic aspects; GTP Phosphohydrolases - immunology; Humans; Immune response; Immune system; Immunology; Immunoprecipitation; Infectious Diseases; Inflammasomes; Inflammasomes - immunology; Innate immunity; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Microtubule-Associated Proteins - immunology; Mitochondria; Mitochondrial Proteins - immunology; Necrosis; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphotransferases; Properties; Real-Time Polymerase Chain Reaction; Receptor-Interacting Protein Serine-Threonine Kinases - immunology; RNA Virus Infections - immunology; RNA Viruses; RNA, Small Interfering; Signal transduction; Signal Transduction - immunology; Threonine; Transfection; Translocation; Viral infections; Viruses
• DOI: 10.1038/ni.3015
• ISSN: 1529-2908; 1529-2916

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.