Journal Article

Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3

Kaiser, William, Rogers, Corey, Wang, Ying, Oberst, Andrew, Green, Douglas R., Fernandes-Alnemri, Teresa, Sagara, Junji, Alnemri, Emad S., Dillon, Christopher, Roback, Linda, Zhang, Jianke, Mayes, Lindsey, Kang, Seokwon, Fitzgerald, Katherine A., Mocarski, Edward S.

2015

Overview

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. Inflammasome activation requires a complex and incompletely understood network of signalling events. Here the authors characterize step-by-step contributions of TLR3, caspase-8, RIPK3 and MLKL to the activation of NLRP3 inflammasome in response to double-stranded RNA.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 13 / 14 / 14/19 / 631/250/256/2177 / 631/250/262/2106 / 631/250/516 / 631/337/458 / 82 / 96 / 96/106 / 96/63 / 96/95 / Adaptor Proteins, Vesicular Transport - genetics / Adaptor Proteins, Vesicular Transport - metabolism / Animals / Carrier Proteins - genetics / Carrier Proteins - metabolism / Caspase 8 - genetics / Caspase 8 - metabolism / Dynamins - genetics / Dynamins - metabolism / Fas-Associated Death Domain Protein - genetics / Fas-Associated Death Domain Protein - metabolism / Humanities and Social Sciences / Macrophages - metabolism / Mice / Mice, Knockout / Mitochondria - metabolism / multidisciplinary / Myeloid Differentiation Factor 88 - genetics / Myeloid Differentiation Factor 88 - metabolism / NLR Family, Pyrin Domain-Containing 3 Protein / Protein Kinases - genetics / Protein Kinases - metabolism / Receptor-Interacting Protein Serine-Threonine Kinases - genetics / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / RNA, Double-Stranded - metabolism / Science / Science (multidisciplinary) / Toll-Like Receptor 3 - metabolism