IRAK-4 Required for Innate Immunity

Science's STKE  23 Apr 2002:
Vol. 2002, Issue 129, pp. tw156
DOI: 10.1126/stke.2002.129.tw156

The Toll-like receptors (TLRs), which are named for their similarity to the receptor Toll in Drosophila that functions in dorsoventral patterning, provide a major interface by which the innate immune system recognizes pathogens. The precise signaling mechanisms activated by these receptors are not known. As in Drosophila, where Toll receptors lead to activation of the Pelle serine-threonine kinase, mammalian TLRs activate interleukin-1 receptor-associated kinases (IRAKs). Suzuki et al. report analysis of mice lacking the IRAK-4 serine-threonine kinase. The animals were completely resistant to what are normally lethal doses of bacterial lipopolysaccharide, recognized by TLR4 proteins. Nor did the animals respond to bacterial DNA through TLR9 proteins. Responses to viral pathogens was also disrupted. The results establish a requirement for IRAK-4 in innate immunity. The exact role of IRAK-4 in TLR signaling remains unclear. The kinase appears to act downstream of the receptor-associated adaptor MyD88 (myeloid differentiation factor 88), but upstream of TRAF6 (tumor necrosis factor receptor-associated factor 6).

N. Suzuki, S. Suzuki, G. S. Duncan, D. G. Millar, T. Wada, C. Mirtsos, H. Takada, A. Wakeham, A. Itie, S. Li, J. M. Pennnger, H. Wesche, P. S. Ohashi, T. W. Mak, W.-C. Yeh. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416, 750-754 (2002). [Online Journal]