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, Emad S. Alnemri

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

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.

Original languageEnglish (US)
Article number7515
JournalNature communications
Volume6
DOIs
StatePublished - Jun 24 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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