Miggin, Sinead and Palsson-McDermott, Eva M. and Dunne, Aisling and Jefferies, Caroline and Pinteaux, Emmanuel and Banahan, Kathy and Murphy, Caroline and Moynagh, Paul N. and Yamamoto, Masahiro and Akira, Shizuo and Rothwell, Nancy and Golenbock, Douglas and Fitzgerald, Katherine A. and O'Neill, Luke A.J. (2007) NF-kB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Proceedings of the National Academy of Sciences, 104 (9). pp. 3372-3377. ISSN 1091-6490

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Abstract

Toll-like receptors (TLRs)-2 and -4 are important proteins in innate immunity, recognizing microbial products and eliciting host defense responses. Both use the adapter proteins MyD88 and MyD88 adapterlike (Mal) to activate signaling pathways. Herewereport that Mal but not MyD88 interacts with caspase-1, the enzyme that processes the precursors of the proinflammatory cytokines IL-1B and IL-18. The interaction was found in a yeast two-hybrid screen and was confirmed by reciprocal GST pull-downs and coimmunoprecipitation of endogenous proteins. We were unable to implicate Mal in regulating caspase-1 activation. However, we found that Mal was cleaved by caspase-1 and that inhibition of caspase-1 activity blocked TLR2- and TLR4-mediated NF-kB and p38 MAP kinase activation but not IL-1 or TLR7 signaling, which are Mal independent. These responses, and the induction of TNF, were also attenuated in caspase-1-deficient cells. Finally, unlike wild-type Mal, a mutant Mal, which was not cleaved by caspase-1, was unable to signal and acted as a dominant negative inhibitor of TLR2 and TLR4 signaling. Our study therefore reveals a role for caspase-1 in the regulation of TLR2 and TLR4 signaling pathways via an effect on Mal. This functional interaction reveals an important aspect of the coordination between TLRs and caspase-1 during the innate response to pathogens.

Item Type:	Article
Keywords:	signaling; Toll-like receptor;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Institute of Immunology
Item ID:	8129
Identification Number:	https://doi.org/10.1073/pnas.0608100104
Depositing User:	Professor Paul Moynagh
Date Deposited:	06 Apr 2017 14:04
Journal or Publication Title:	Proceedings of the National Academy of Sciences
Publisher:	National Academy of Sciences
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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