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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).
Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A. & Bazan, J. F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl Acad. Sci. USA 95, 588–593 (1998).
Brightbill, H. D. et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285, 732–736 (1999).
Aliprantis, A. O. et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285, 736–739 (1999).
Underhill, D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811–815 (1999).
Ozinsky, A. et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc. Natl Acad. Sci. USA 97, 13766–13771 (2000).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001).
Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).
Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612–1615 (1997).
Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997).
Kirschning, C. J., Wesche, H., Merrill Ayres, T. & Rothe, M. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J. Exp. Med. 188, 2091–2097 (1998).
Muzio, M., Natoli, G., Saccani, S., Levrero, M. & Mantovani, A. The human toll signaling pathway: divergence of nuclear factor κB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J. Exp. Med. 187, 2097–2101 (1998).
Schnare, M., Holt, A. C., Takeda, K., Akira, S. & Medzhitov, R. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr. Biol. 10, 1139–1142 (2000).
Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K. & Akira, S. Endotoxin-induced maturation of myd88-deficient dendritic cells. J. Immunol. 166, 5688–5694 (2001).
Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999).
Cosman, D. et al. Cloning, sequence and expression of human interleukin-2 receptor. Nature 312, 768–771 (1984).
Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000).
Jefferies, C. et al. Transactivation by the p65 subunit of NF-κB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1. Mol. Cell. Biol. 21, 4544–4552 (2001).
Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1240 (2000).
Yamaguchi, K. et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270, 2008–2011 (1995).
Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998).
Bowie, A. et al. A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc. Natl Acad. Sci. USA 97, 10162–10167 (2000).
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/35092578
This article is cited by
-
MyD88 in myofibroblasts enhances nonalcoholic fatty liver disease-related hepatocarcinogenesis via promoting macrophage M2 polarization
Cell Communication and Signaling (2024)
-
POU5F1 promotes the proliferation, migration, and invasion of gastric cancer cells by reducing the ubiquitination level of TRAF6
Cell Death & Disease (2023)
-
Incomplete Knockdown of MyD88 Inhibits LPS-Induced Lung Injury and Lung Fibrosis in a Mouse Model
Inflammation (2023)
-
MyD88 in hepatic stellate cells enhances liver fibrosis via promoting macrophage M1 polarization
Cell Death & Disease (2022)
-
Protein N-myristoylation: functions and mechanisms in control of innate immunity
Cellular & Molecular Immunology (2021)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.