IRAK-4 as the central TIR signaling mediator in innate immunity |
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Authors: | Suzuki Nobutaka Suzuki Shinobu Yeh Wen-Chen |
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Affiliation: | Ontario Cancer Institute and Dept of Medical Biophysics, University of Toronto 620 University Avenue, Ontario, M5G 2C1, Toronto, Canada. |
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Abstract: | 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. |
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Keywords: | IRAK-4 TLR TIR IRAK family IL-1R innate immunity TIR signaling LPS signaling Immunology Cell biology Biochemistry |
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