Depart of Medicine, Division of Infectious Diseases and Immunology
Immunity | Molecular Biology
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.
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DOI of Published Version
Nat Commun. 2015 Jun 24;6:7515. doi: 10.1038/ncomms8515. Link to article on publisher's site
Kang S, Fernandes-Alnemri T, Rogers C, Mayes L, Wang Y, Dillon CP, Roback L, Kaiser W, Oberst A, Sagara J, Fitzgerald KA, Green DR, Zhang J, Mocarski ES, Alnemri ES. (2015). Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Open Access Articles. https://doi.org/10.1038/ncomms8515. Retrieved from https://escholarship.umassmed.edu/oapubs/2707
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.