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

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 UniversityFollow
• Lindsey Mayes, Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
• 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.

Recommended Citation

Kang, Seokwon; Fernandes-Alnemri, Teresa; Rogers, Corey; Mayes, Lindsey; Wang, Ying; Dillon, Christopher; Roback, Linda; Kaiser, William; Oberst, Andrew; Sagara, Junji; Fitzgerald, Katherine A; Green, Douglas R; Zhang, Jianke; Mocarski, Edward S; and Alnemri, Emad S, "Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3." (2015). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 89.
https://jdc.jefferson.edu/bmpfp/89

PubMed ID

26104484