Main content area

NF-κB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1

Miggin, Sinead M., Pålsson-McDermott, Eva, Dunne, Aisling, Jefferies, Caroline, Pinteaux, Emmanuel, Banahan, Kathy, Murphy, Caroline, Moynagh, Paul, Yamamoto, Masahiro, Akira, Shizuo, Rothwell, Nancy, Golenbock, Douglas, Fitzgerald, Katherine A., O'Neill, Luke A.J.
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.9 pp. 3372-3377
Toll-like receptor 2, Toll-like receptor 4, Toll-like receptor 7, caspase-1, innate immunity, interleukin-18, interleukin-1beta, mitogen-activated protein kinase, mutants, pathogens, signal transduction, transcription factor NF-kappa B, tumor necrosis factors, two hybrid system techniques
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.