NF-κB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1
| Autor: | Shizuo Akira, Kathy Banahan, Paul N. Moynagh, Katherine A. Fitzgerald, Nancy J. Rothwell, Douglas T. Golenbock, Masahiro Yamamoto, Luke A. J. O'Neill, Emmanuel Pinteaux, Sinead M. Miggin, Aisling Dunne, Caroline Murphy, Caroline A. Jefferies, Eva M. Palsson-McDermott |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Immunoblotting
Caspase 1 Electrophoretic Mobility Shift Assay Biology Two-Hybrid System Techniques Humans Immunoprecipitation DNA Primers Toll-like receptor Multidisciplinary Innate immune system Membrane Glycoproteins NF-kappa B Signal transducing adaptor protein Receptors Interleukin-1 TLR7 Biological Sciences Toll-Like Receptor 2 Cell biology Toll-Like Receptor 4 TLR2 Myeloid Differentiation Factor 88 Signal transduction Signal Transduction |
| Popis: | 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-1β 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-κB 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. |
| Databáze: | OpenAIRE |
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