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

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

doi:10.1038/ni.3015

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

Nat Immunol. 2014 Dec;15(12):1126-33. doi: 10.1038/ni.3015. Epub 2014 Oct 19.

Authors

Xiaqiong Wang¹, Wei Jiang¹, Yiqing Yan¹, Tao Gong¹, Jiahuai Han², Zhigang Tian³, Rongbin Zhou³

Affiliations

¹ 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.
² State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Biology, Xiamen University, Xiamen, Fujian, China.
³ 1] 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. [2] Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.

PMID: 25326752
DOI: 10.1038/ni.3015

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carrier Proteins / immunology*
Cell Line
Dynamins / immunology
Enzyme-Linked Immunosorbent Assay
GTP Phosphohydrolases / immunology
Humans
Immunoprecipitation
Inflammasomes / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Microtubule-Associated Proteins / immunology
Mitochondrial Proteins / immunology
NLR Family, Pyrin Domain-Containing 3 Protein
RNA Virus Infections / immunology*
RNA Viruses
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
Signal Transduction / immunology*
Transfection

Substances

Carrier Proteins
Inflammasomes
Microtubule-Associated Proteins
Mitochondrial Proteins
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
RNA, Small Interfering
RIPK1 protein, human
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk1 protein, mouse
GTP Phosphohydrolases
DNM1L protein, human
Dnm1l protein, mouse
Dynamins