Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction
Department of Medicine, Division of Infectious Diseases and Immunology
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
Immunology and Infectious Disease
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.
DOI of Published Version
Nature. 2001 Sep 6;413(6851):78-83. Link to article on publisher's site
Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint EK, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA. (2001). Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Infectious Diseases and Immunology Publications. https://doi.org/10.1038/35092578. Retrieved from https://escholarship.umassmed.edu/infdis_pp/126