PMID:11544529

Citation	Fitzgerald, KA, Palsson-McDermott, EM, Bowie, AG, Jefferies, CA, Mansell, AS, Brady, G, Brint, E, Dunne, A, Gray, P, Harte, MT, McMurray, D, Smith, DE, Sims, JE, Bird, TA and O'Neill, LA (2001) Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78-83
Abstract	The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. 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-kappaB, 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-kappaB 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-kappaB, which is activated by TLR-4 or lipopolysaccharide, 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 transduction.
Links	PubMed Online version:10.1038/35092578
Keywords	Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Antigens, Differentiation/chemistry; Antigens, Differentiation/metabolism; Carrier Proteins/genetics; Carrier Proteins/physiology; Cell Line; Drosophila Proteins; Humans; Interleukin-1 Receptor-Associated Kinases; Lipopolysaccharides/metabolism; Membrane Glycoproteins/metabolism; Mice; Molecular Sequence Data; Myeloid Differentiation Factor 88; NF-kappa B/metabolism; Protein Kinases/metabolism; RNA, Messenger/metabolism; Receptors, Cell Surface/metabolism; Receptors, Immunologic; Receptors, Interleukin-1; Sequence Homology, Amino Acid; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9; Toll-Like Receptors; Transfection; Xenopus; Xenopus Proteins
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