The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling.
Interleukin 1 receptor (IL-1R)-associated kinase-4 (IRAK-4) is required for various responses induced by IL-1R and Toll-like receptor signals. However, the molecular mechanism of IRAK-4 signaling and the role of its kinase activity have remained elusive. In this report, we demonstrate that IRAK-4 is recruited to the IL-1R complex upon IL-1 stimulation and is required for the recruitment of IRAK-1 and its subsequent activation/degradation. By reconstituting IRAK-4-deficient cells with wild type or kinase-inactive IRAK-4, we show that the kinase activity of IRAK-4 is required for the optimal transduction of IL-1-induced signals, including the activation of IRAK-1, NF-kappaB, and JNK, and the maximal induction of inflammatory cytokines. Interestingly, we also discover that the IRAK-4 kinase-inactive mutant is still capable of mediating some signals. These results suggest that IRAK-4 is an integral part of the IL-1R signaling cascade and is capable of transmitting signals both dependent on and independent of its kinase activity.
Lye
Elizabeth
E
Advanced Medical Discovery Institute, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Mirtsos
Christine
C
Suzuki
Nobutaka
N
Suzuki
Shinobu
S
Yeh
Wen-Chen
WC
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003001:Cloning, Molecular; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism / Q000502:physiology*; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D014162:Transfection; D019076:Transgenes
D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D011994:Recombinant Proteins; D008156:Luciferases; D017853:Phosphotransferases (Alcohol Group Acceptor); C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases