Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (1-9). Different TLRs recognize different pathogen-associated mole cular patterns, with TLR-4 mediating the response to lipopolysaccharide fro m Gram-negative bacteria(5-7). All TLRs have a Toll/IL-1 receptor (TIR) dom ain, which is responsible for signal transduction(1,2). MyD88 is one such p rotein that contains a TIR domain(10,11). It acts as an adapter, being invo lved in TLR-2, TLR-4 and TLR-9 signalling(12-15); however, our understandin g of how TLR-4 signals is incomplete(15,16). Here we describe a protein, Ma l (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-conta ining protein in the human genome. Mal activates NF-kappaB, Jun amino-termi nal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kap paB 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 negativ e form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysa ccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal tra nsduction.