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XB-ART-8452
Nature September 6, 2001; 413 (6851): 78-83.

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

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 , O'Neill LA .


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.

PubMed ID: 11544529
Article link: Nature

Genes referenced: il1b irak1 irak2 jun mal myd88 nfkb1 tirap



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