title: Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.
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.
authors.affiliation: Department of Biochemistry, Trinity College, Dublin 2, Ireland.
authors.forename: K A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: E M
authors.initials: EM
authors.lastname: Palsson-McDermott
authors.forename: A G
authors.initials: AG
authors.lastname: Bowie
authors.forename: C A
authors.initials: CA
authors.lastname: Jefferies
authors.forename: A S
authors.initials: AS
authors.lastname: Mansell
authors.forename: G
authors.initials: G
authors.lastname: Brady
authors.forename: E
authors.initials: E
authors.lastname: Brint
authors.forename: A
authors.initials: A
authors.lastname: Dunne
authors.forename: P
authors.initials: P
authors.lastname: Gray
authors.forename: M T
authors.initials: MT
authors.lastname: Harte
authors.forename: D
authors.initials: D
authors.lastname: McMurray
authors.forename: D E
authors.initials: DE
authors.lastname: Smith
authors.forename: J E
authors.initials: JE
authors.lastname: Sims
authors.forename: T A
authors.initials: TA
authors.lastname: Bird
authors.forename: L A
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D029721:Drosophila Proteins; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014162:Transfection; D014981:Xenopus; D029867:Xenopus Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D002352:Carrier Proteins; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C499316:MyD88 protein, Xenopus; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C499045:TIRAP protein, mouse; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D029867:Xenopus Proteins; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases