1. Department of Biochemistry, Trinity College, Dublin 2, Ireland
2. Immunex Corporation, Seattle, Washington 98101, USA
3. These authors contributed equally to this work
4. Present address: Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.

Correspondence to: Luke A. J. O'Neill¹ Correspondence and requests for materials should be addressed to L.A.J.O. (e-mail: Email: laoneill@tcd.ie).

Abstract

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns^{1, 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 bacteria^{5, 6, 7}. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction^{1, 2}. MyD88 is one such protein that contains a TIR domain^{10, 11}. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling^{12, 13, 14, 15}; however, our understanding of how TLR-4 signals is incomplete^{15, 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-B, 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-B 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-B, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-B activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.