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

Nature volume 413, pages 78–83 (2001)Cite this article

Abstract

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns1,2,3,4,5,6,7,8,9. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria5,6,7. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction1,2. MyD88 is one such protein that contains a TIR domain10,11. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling12,13,14,15; however, our understanding of how TLR-4 signals is incomplete15,16. 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-κB, 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-κB 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-κB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-κB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.

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Figure 1: MyD88-adapter-like (Mal) is a widely expressed homologue of MyD88.
Figure 2: Mal overexpression activated NF-κB, JNK and ERK1/2.
Figure 3: Mal signals by means of MyD88, IRAK-2, TRAF-6 and TAK.
Figure 4: Mal is required for TLR-4 and LPS signalling.

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Acknowledgements

We thank K. Mills for DC samples; M. Muzio for plasmids encoding MyD88, IRAK-2 and TLR-4; E. L. Cooke for plasmids encoding IRAK (1–211); W. Falk for plasmids encoding IL-1R1 and IL-1RacP; and H. Sakurai at Tanabe Seiyaku, Japan, for plasmids encoding TAK-1k63w. We also thank D. Caffrey for advice on alignments, E. Kurt-Jones for HEK293 cells stably transfected with Flag-TLR-4 and CD14, and P. Henneke and D. Golenbock for helpful discussions. This work was supported by the European Union Biomed, Biotech and TMR programmes, Enterprise Ireland and the National Pharmaceutical Biotechnology Centre.

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  1. Andrew G. Bowie

    Present address: Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, 4, Ireland

  2. Katherine A. Fitzgerald and Eva M. Palsson-McDermott: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry, Trinity College, Dublin, 2, Ireland

    Katherine A. Fitzgerald, Eva M. Palsson-McDermott, Andrew G. Bowie, Caroline A. Jefferies, Ashley S. Mansell, Gareth Brady, Elizabeth Brint, Aisling Dunne, Pearl Gray, Mary T. Harte & Luke A. J. O'Neill

  2. Immunex Corporation, Seattle, 98101, Washington, USA

    Diane McMurray, Dirk E. Smith, John E. Sims & Timothy A. Bird

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Fitzgerald, K., Palsson-McDermott, E., Bowie, A. et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78–83 (2001). https://doi.org/10.1038/35092578

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