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Nat Commun. 2015 Jun 24;6:7515. doi: 10.1038/ncomms8515.

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

Author information

1
Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
2
Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York 10032, USA.
3
Deptartment of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
4
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
5
Department of Immunology, University of Washington, Seattle Washington 98109-8059 USA.
6
Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University, Matsumoto, Nagano 390-8621, Japan.
7
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
8
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

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.

PMID:
26104484
PMCID:
PMC4480782
DOI:
10.1038/ncomms8515
[Indexed for MEDLINE]
Free PMC Article

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