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- Title
Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.
- Authors
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
- 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.
- Publication
Nature, 2001, Vol 413, Issue 6851, p78
- ISSN
0028-0836
- Publication type
Journal Article
- DOI
10.1038/35092578