Mal (MyD88-adapter-like) is required for toll-like recepfor-4 signal transduction

Katherine A. Fitzgerald, Eva M. Palsson-Mcdermott, Andrew G. Bowie, Caroline A. Jefferies, Ashley S. Mansell, Gareth Brady, Elizabeth Brint, Aisling Dunne, Pearl Gray, Mary T. Harte, Diane McMurray, Dirk E. Smith, John E. Sims, Timothy A. Bird, Luke A.J. O'Neill

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Abstract

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns1-9. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria5-7. All TLRs have a Toll/IL-1 receptor (TLR) domain, which is responsible for signal transduction1,2. MyD88 is one such protein that contains a TlR domain10,11. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling12-15; however, our understanding of how TLR-4 signals is incomplete15,16. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-κB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-κB by Mai requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TlR domain. A dominant negative form of Mal inhibits NF-κB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-κB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.

Original languageEnglish
Pages (from-to)78-83
Number of pages6
JournalNature
Volume413
Issue number6851
DOIs
Publication statusPublished - 6 Sep 2001
Externally publishedYes

Cite this

Fitzgerald, K. A., Palsson-Mcdermott, E. M., Bowie, A. G., Jefferies, C. A., Mansell, A. S., Brady, G., Brint, E., Dunne, A., Gray, P., Harte, M. T., McMurray, D., Smith, D. E., Sims, J. E., Bird, T. A., & O'Neill, L. A. J. (2001). Mal (MyD88-adapter-like) is required for toll-like recepfor-4 signal transduction. Nature, 413(6851), 78-83. https://doi.org/10.1038/35092578