Abstract
Mammalian Toll-like receptors (TLRs) recognize conserved products of microbial metabolism and activate NF-κB and other signaling pathways through the adapter protein MyD88. Although some cellular responses are completely abolished in MyD88-deficient mice, TLR4, but not TLR9, can activate NF-κB and mitogen-activated protein kinases and induce dendritic cell maturation in the absence of MyD88. These differences suggest that another adapter must exist that can mediate MyD88-independent signaling in response to TLR4 ligation. We have identified and characterized a Toll–interleukin 1 receptor (TIR) domain–containing adapter protein (TIRAP) and have shown that it controls activation of MyD88-independent signaling pathways downstream of TLR4. We have also shown that the double-stranded RNA-binding protein kinase PKR is a component of both the TIRAP- and MyD88-dependent signaling pathways.
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Acknowledgements
We thank S. Akira for MyD88-deficient mice; M. Katze and L. Jensen for p58 and IL-1R plasmids; and L. Kopp for helpful discussions and critical reading of the manuscript. Supported by NIH grant AI44220-01, the Searle Foundation (R. M.) and the Howard Hughes Medical Institute (R. M. and T. H.).
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Horng, T., Barton, G. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2, 835–841 (2001). https://doi.org/10.1038/ni0901-835
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DOI: https://doi.org/10.1038/ni0901-835