title: Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome.
abstract: Activation of the NLRP3 inflammasome by diverse stimuli requires a priming signal from TLRs and an activation signal from purinergic receptors or pore-forming toxins. In this study, we demonstrate, through detailed analysis of NLRP3 activation in macrophages deficient in key downstream TLR signaling molecules, that MyD88 is required for an immediate early phase, whereas Toll/IL-1R domain-containing adapter inducing IFN-β is required for a subsequent intermediate phase of posttranslational NLRP3 activation. Both IL-1R-associated kinase (IRAK) 1 and IRAK4 are critical for rapid activation of NLRP3 through the MyD88 pathway, but only IRAK1 is partially required in the Toll/IL-1R domain-containing adapter inducing IFN-β pathway. IRAK1 and IRAK4 are also required for rapid activation of NLRP3 by Listeria monocytogenes, as deletion of IRAK1 or IRAK4 led to defective inflammasome activation. These findings define the pathways that lead to rapid NLRP3 activation and identify IRAK1 as a critical mediator of a transcription-independent,inflammasome-dependent early warning response to pathogenic infection.
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.forename: Seokwon
authors.initials: S
authors.lastname: Kang
authors.forename: Connor
authors.initials: C
authors.lastname: Anderson
authors.forename: Junji
authors.initials: J
authors.lastname: Sagara
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D058847:Inflammasomes; D016899:Interferon-beta / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology* / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D058847:Inflammasomes; D016899:Interferon-beta; D053592:Interleukin-1 Receptor-Associated Kinases; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C492716:Nlrp3 protein, mouse; C476286:Ticam1 protein, mouse; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse
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