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

• Type of Material: Article
• Authors: Seokwon Kang, Thomas Jefferson University; Teresa Fernandes-Alnemri, Thomas Jefferson University; Corey Rogers, Thomas Jefferson University; Lindsey Mayes, Thomas Jefferson University; Ying Wang, Columbia University; Christopher Dillon, St Jude Children's Research Hospital; Linda Roback, Emory University; William Kaiser, Emory University; Andrew Oberst, University of Washington; Junji Sagara, Shinshu University; Katherine A. Fitzgerald, University of Massachusetts; Douglas R. Green, St Jude Children's Research Hospital; Jianke Zhang, Thomas Jefferson University; Edward Mocarski, Emory University; Emad S. Alnemri, Thomas Jefferson University
• Language: English
• Date: 2015-06-24
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms8515
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 6
• Grant/Funding Information: C.R. was supported by NIH training grant T32 GM100836.; Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number AR055398 to ESA.
• Keywords: APOPTOSIS; TOLL-LIKE RECEPTORS; SIGNALING PATHWAY; Signal transduction; Science & Technology; RIP3 KINASE; PROGRAMMED NECROSIS; Post-translational modifications; ASC PYROPTOSOME; Pattern recognition receptors; Multidisciplinary Sciences; Science & Technology - Other Topics; CELL-DEATH; Inflammasome; PATTERN-RECOGNITION; LISTERIA-MONOCYTOGENES; K+ EFFLUX
• Research Categories: Health Sciences, Immunology; Biology, Cell; Biology, Microbiology

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.