title: NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1.
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 adapter-like (Mal) to activate signaling pathways. Here we report that Mal but not MyD88 interacts with caspase-1, the enzyme that processes the precursors of the proinflammatory cytokines IL-1beta 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-kappaB 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.
authors.affiliation: School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Miggin
authors.forename: Eva
authors.initials: E
authors.lastname: Pålsson-McDermott
authors.forename: Aisling
authors.initials: A
authors.lastname: Dunne
authors.forename: Caroline
authors.initials: C
authors.lastname: Jefferies
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinteaux
authors.forename: Kathy
authors.initials: K
authors.lastname: Banahan
authors.forename: Caroline
authors.initials: C
authors.lastname: Murphy
authors.forename: Paul
authors.initials: P
authors.lastname: Moynagh
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Nancy
authors.initials: N
authors.lastname: Rothwell
authors.forename: Douglas
authors.initials: D
authors.lastname: Golenbock
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D020170:Caspase 1 / Q000378:metabolism*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D017931:DNA Primers; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020170:Caspase 1