Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction
AuthorsFitzgerald, Katherine A.
Palsson-McDermott, Eva M.
Bowie, Andrew G.
Jefferies, Caroline A.
Mansell, Ashley S.
Brint, Elizabeth K.
Harte, Mary T.
Smith, Dirk E.
Sims, John E.
Bird, Timothy A.
O'Neill, Luke A. J.
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
Document TypeJournal Article
KeywordsAdaptor Proteins, Signal Transducing
Amino Acid Sequence
Interleukin-1 Receptor-Associated Kinases
Molecular Sequence Data
Myeloid Differentiation Factor 88
Receptors, Cell Surface
Sequence Homology, Amino Acid
Toll-Like Receptor 2
Toll-Like Receptor 4
Toll-Like Receptor 9
Immunology and Infectious Disease
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AbstractThe 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.
SourceNature. 2001 Sep 6;413(6851):78-83. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/34899
Related ResourcesLink to Article in PubMed
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