Year: 2019
Type: preprint
Abstract: Summary The innate immune system signals through various higher order signaling complexes called supramolecular organizing centers (SMOCs), which typically organize components of a single pathway. While innate immune signaling pathways have been largely characterized using single receptor stimuli, responses to pathogens require the coordinated engagement of multiple pathways. Here, we report an IRAK1-containing SMOC formed specifically when multiple receptors are activated, which recruits select components of the TLR, MAPK and inflammasome pathways. This allows for signal flux redistribution from TLRs to inflammasomes and facilitates inflammasome licensing through an MKK7-JNK axis, which is defective in Irak1 −/− mice. Furthermore, this defect in Irak1 −/− mice manifests in increased susceptibility to inflammasome-sensitive pathogens and diminished IL1 production from inflammasomes after co-TLR priming. Thus, IRAK1 SMOCs form a multi-pathway coordinating hub for coincidence detection of microbial signals, which may be employed by innate immune cells as a threat assessment and thresholding mechanism for inflammasome activation.
Authors: Sharat J. Vayttaden, Margery Smelkinson, Orna Ernst, Rebecca J. Carlson, Jing Sun, Clinton Bradfield, Michael G. Dorrington, Jonathan Liang, Nicolas Bouladoux, Rachel A. Gottschalk, Kyu-Seon Oh, Gianluca Pegoraro, Sundar Ganesan, Dominic De Nardo, Eicke Latz, Yasmine Belkaid, Rajat R. Varma, Iain D.C. Fraser
Institutions: National Institute of Allergy and Infectious Diseases, Broad Institute, Massachusetts Institute of Technology, University of Pittsburgh, National Institutes of Health, National Institute on Aging, National Cancer Institute, Center for Cancer Research, University of Bonn, University Hospital Bonn, Monash University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2997573854