Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction
Authors
Fitzgerald, Katherine A.Palsson-McDermott, Eva M.
Bowie, Andrew G.
Jefferies, Caroline A.
Mansell, Ashley S.
Brady, Gerard
Brint, Elizabeth K.
Dunne, Aisling
Gray, Pearl
Harte, Mary T.
McMurray, Diane
Smith, Dirk E.
Sims, John E.
Bird, Timothy A.
O'Neill, Luke A. J.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2001-09-07Keywords
Adaptor Proteins, Signal TransducingAmino Acid Sequence
Animals
Antigens, Differentiation
Carrier Proteins
Cell Line
*Drosophila Proteins
Humans
Interleukin-1 Receptor-Associated Kinases
Lipopolysaccharides
Membrane Glycoproteins
Mice
Molecular Sequence Data
Myeloid Differentiation Factor 88
NF-kappa B
Protein Kinases
RNA, Messenger
Receptors, Cell Surface
*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
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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.Source
Nature. 2001 Sep 6;413(6851):78-83. Link to article on publisher's siteDOI
10.1038/35092578Permanent Link to this Item
http://hdl.handle.net/20.500.14038/34899PubMed ID
11544529Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/35092578
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