Abstract
TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activation through intermediate and late TRIF/RIPK1/FADD-dependent pathways. Both pathways require the scaffolding but not the catalytic function of caspase-8 or RIPK1. Only the late pathway requires kinase competent RIPK3 and MLKL function. Mechanistically, FADD/caspase-8 scaffolding function provides a post-translational signal 1 in the intermediate pathway, whereas in the late pathway it helps the oligomerization of RIPK3, which together with MLKL provides both signal 1 and 2 for inflammasome assembly. Cytoplasmic dsRNA activates NLRP3 independent of TRIF, RIPK1, RIPK3 or mitochondrial DRP1, but requires FADD/caspase-8 in wildtype macrophages to remove RIPK3 inhibition. Our study provides a comprehensive analysis of pathways that lead to NLRP3 inflammasome activation in response to dsRNA.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 8 / genetics
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Caspase 8 / metabolism*
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Dynamins / genetics
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Dynamins / metabolism
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Fas-Associated Death Domain Protein / genetics
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Fas-Associated Death Domain Protein / metabolism
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Macrophages / metabolism*
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Mice
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Mice, Knockout
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Mitochondria / metabolism
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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RNA, Double-Stranded / metabolism*
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Toll-Like Receptor 3 / metabolism*
Substances
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Adaptor Proteins, Vesicular Transport
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Carrier Proteins
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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RNA, Double-Stranded
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TICAM-1 protein, mouse
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TLR3 protein, mouse
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Toll-Like Receptor 3
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MLKL protein, mouse
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Protein Kinases
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk1 protein, mouse
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Ripk3 protein, mouse
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Casp8 protein, mouse
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Caspase 8
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Dnm1l protein, mouse
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Dynamins