Authors

Seokwon Kang, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University
Teresa Fernandes-Alnemri, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Corey Rogers, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University
Lindsey Mayes, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University
Ying Wang, Department of Physiology and Cellular Biophysics, Columbia University Medical Center
Christopher Dillon, Deptartment of Immunology, St Jude Children's Research Hospital
Linda Roback, Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine
William Kaiser, Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine
Andrew Oberst, Department of Immunology, University Of Washington
Junji Sagara, Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University, Matsumoto
Katherine A Fitzgerald, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School
Douglas R Green, Deptartment of Immunology, St Jude Children's Research Hospital
Jianke Zhang, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Edward S Mocarski, Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine
Emad S Alnemri, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

6-24-2015

Comments

This article has been peer reviewed. It was published in: Nature Communications.

Volume 6, 24 June 2015, Article number 7515.

The published version is available at DOI: 10.1038/ncomms8515

Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

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.

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.