Mal (MyD88-adapter-like) is required for Toll-like receptor-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 and Luke A. J. O'Neill ()
Additional contact information
Katherine A. Fitzgerald: Trinity College
Eva M. Palsson-McDermott: Trinity College
Andrew G. Bowie: Trinity College
Caroline A. Jefferies: Trinity College
Ashley S. Mansell: Trinity College
Gareth Brady: Trinity College
Elizabeth Brint: Trinity College
Aisling Dunne: Trinity College
Pearl Gray: Trinity College
Mary T. Harte: Trinity College
Diane McMurray: Immunex Corporation
Dirk E. Smith: Immunex Corporation
John E. Sims: Immunex Corporation
Timothy A. Bird: Immunex Corporation
Luke A. J. O'Neill: Trinity College

Nature, 2001, vol. 413, issue 6851, 78-83

Abstract: Abstract The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns1,2,3,4,5,6,7,8,9. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria5,6,7. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction1,2. MyD88 is one such protein that contains a TIR domain10,11. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling12,13,14,15; 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 TIR-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 Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR 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.

Date: 2001
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DOI: 10.1038/35092578

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