Type

Journal Article

Authors

Luke A.J. O'Neill
Katherine A. Fitzgerald
Douglas Golenbock
Nancy Rothwell
Shizuo Akira
Masahiro Yamamoto
Paul N. Moynagh
Caroline Murphy
Kathy Banahan
Emmanuel Pinteaux
and 4 others

Subjects

Biochemistry

Topics
yeast two hybrid toll like receptor 1 nf kb toll like receptors tlrs receptor activation 1 protein il 1 caspase 1

NF-kB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1 (2007)

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.
Collections Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering: Research Institutes: Institute of Immunology
Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering: Biology
Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering: Research Institutes
Ireland -> Maynooth University -> Type = Article
Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering
Ireland -> Maynooth University -> Status = Published
Ireland -> Maynooth University -> Open Access DRIVERset

Full list of authors on original publication

Luke A.J. O'Neill, Katherine A. Fitzgerald, Douglas Golenbock, Nancy Rothwell, Shizuo Akira, Masahiro Yamamoto, Paul N. Moynagh, Caroline Murphy, Kathy Banahan, Emmanuel Pinteaux and 4 others

Experts in our system

1
Luke Anthony John O'Neill
Trinity College Dublin
Total Publications: 262
 
2
Paul N. Moynagh
Maynooth University
Total Publications: 91
 
3
Kathy Banahan
Trinity College Dublin
Total Publications: 4