IRAK-4 as the central TIR signaling mediator in innate immunity.
Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns and members of the proinflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains. Engagement of members of both of these families initiates a common intracellular signaling cascade, in which MyD88 and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) are key adaptor proteins. Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement. The kinase activity of IRAK-4 might be necessary to functionally modify IRAK-1 and perhaps other signal transducing substrates. Understanding the role of IRAK-4 in innate immunity will enable us to design novel strategies for therapeutic intervention in human infectious disease.
Suzuki
Nobutaka
N
Ontario Cancer Institute and Dept of Medical Biophysics, University of Toronto 620 University Avenue, Ontario, M5G 2C1, Toronto, Canada.
Suzuki
Shinobu
S
Yeh
Wen-Chen
WC
D000818:Animals; D029721:Drosophila Proteins; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology*; D018448:Models, Immunological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D015398:Signal Transduction; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases