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

Seokwon Kang, Teresa Fernandes-Alnemri (), Corey Rogers, Lindsey Mayes, Ying Wang, Christopher Dillon, Linda Roback, William Kaiser, Andrew Oberst, Junji Sagara, Katherine A. Fitzgerald, Douglas R. Green, Jianke Zhang, Edward S. Mocarski and Emad S. Alnemri ()
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Seokwon Kang: Kimmel Cancer Center, Thomas Jefferson University
Teresa Fernandes-Alnemri: Kimmel Cancer Center, Thomas Jefferson University
Corey Rogers: Kimmel Cancer Center, Thomas Jefferson University
Lindsey Mayes: Kimmel Cancer Center, Thomas Jefferson University
Ying Wang: Columbia University Medical Center
Christopher Dillon: Deptartment of Immunology, St Jude Children's Research Hospital
Linda Roback: Emory Vaccine Center, Emory University School of Medicine
William Kaiser: Emory Vaccine Center, Emory University School of Medicine
Andrew Oberst: University of Washington
Junji Sagara: School of Health Sciences, Shinshu University
Katherine A. Fitzgerald: University of Massachusetts Medical School
Douglas R. Green: Deptartment of Immunology, St Jude Children's Research Hospital
Jianke Zhang: Kimmel Cancer Center, Thomas Jefferson University
Edward S. Mocarski: Emory Vaccine Center, Emory University School of Medicine
Emad S. Alnemri: Kimmel Cancer Center, Thomas Jefferson University

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8515

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