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

K A Fitzgerald, E M Palsson-McDermott, A G Bowie, C A Jefferies, A S Mansell, G Brady, E Brint, A Dunne, P Gray, M T Harte, D McMurray, D E Smith, J E Sims, T A Bird, L A O'Neill

Research output: Contribution to journalArticle

933 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)78-83
Number of pages6
JournalNature
Volume413
Issue number6851
DOIs
Publication statusPublished - 06 Sep 2001

Keywords

  • Adaptor Proteins, Signal Transducing
  • Amino 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

Fingerprint Dive into the research topics of 'Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction'. Together they form a unique fingerprint.

  • Cite this

    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. (2001). Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature, 413(6851), 78-83. https://doi.org/10.1038/35092578