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TIRAP: an adapter molecule in the Toll signaling pathway

Nature Immunology volume 2, pages 835–841 (2001)Cite this article

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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Figure 1: Sequence alignment of human and mouse TIRAP. Amino acid sequence comparison of human (h TIRAP) and mouse (m TIRAP) TIRAP.
Figure 2: TIRAP is a component of the TLR4 signaling pathway, but not of the IL-1R or TLR9 signaling pathways.
Figure 3: Wild-type TIRAP but not TIRAP-P125H immunoprecipitates with TLR4.
Figure 4: PKR is a component of LPS- and CpG-signaling pathways and immunoprecipitates with TIRAP.
Figure 5: The cell permeable TIRAP peptide inhibited LPS-, but not CpG-, induced NF-κB activation, PKR phosphorylation and Jnk phosphorylation.
Figure 6: TIRAP controls DC maturation.

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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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  1. Tiffany Horng and Gregory M. Barton: These authors contributed equally to this work.

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  1. Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, 06520, CT, USA

    Tiffany Horng, Gregory M. Barton & Ruslan Medzhitov

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Correspondence to Ruslan Medzhitov.

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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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