Abstract
Interleukin-1 (IL-1) stimulation leads to the recruitment of interleukin-1 receptor-associated kinase (IRAK) to the IL-1 receptor, where IRAK is phosphorylated, ubiquitinated, and eventually degraded. Kinase-inactive mutant IRAK is still phosphorylated in response to IL-1 stimulation when it is transfected into IRAK-deficient cells, suggesting that there must be an IRAK kinase in the pathway. The fact that IRAK4, another IRAK family member necessary for the IL-1 pathway, is able to phosphorylate IRAK in vitro suggests that IRAK4 might be the IRAK kinase. However, we now found that the IRAK4 kinase-inactive mutant had the same ability as the wild-type IRAK4 in restoring IL-1-mediated signaling in human IRAK4-deficient cells, including NFkappaB-dependent reporter gene expression, the activation of NFkappaB and JNK, and endogenous IL-8 gene expression. These results strongly indicate that the kinase activity of human IRAK4 is not necessary for IL-1 signaling. Furthermore, we showed that the kinase activity of IRAK4 was not necessary for IL-1-induced IRAK phosphorylation, suggesting that IRAK phosphorylation can probably be achieved either by autophosphorylation or by trans-phosphorylation through IRAK4. In support of this, only the impairment of the kinase activity of both IRAK and IRAK4 efficiently abolished the IL-1 pathway, demonstrating that the kinase activity of IRAK and IRAK4 is redundant for IL-1-mediated signaling. Moreover, consistent with the fact that IRAK4 is a necessary component of the IL-1 pathway, we found that IRAK4 was required for the efficient recruitment of IRAK to the IL-1 receptor complex.
Highlights
The Toll-IL-11 receptor superfamily, a large family of proteins defined by the presence of an intracellular Toll-IL-1 receptor (TIR) domain, plays crucial roles in the immune responses
The Kinase Activity of Human IRAK4 Is Dispensable for IL-1mediated Signaling—Severe impairment of IL-1R/Toll-like receptors (TLRs)-mediated signaling is observed in mice lacking IRAK4 and in IRAK4deficient cells derived from human patients, indicating that IRAK4 is required for IL-1-mediated signaling [16, 17, 26]
We showed that IRAK4 kinase-inactive mutant had the same ability as the wild-type IRAK4 in restoring IL-1-mediated signaling in IRAK4-deficient cells, indicating that the kinase activity of IRAK4 is not necessary for the IL-1 pathway
Summary
The Toll-IL-11 receptor superfamily, a large family of proteins defined by the presence of an intracellular Toll-IL-1 receptor (TIR) domain, plays crucial roles in the immune responses. This superfamily can be divided into two main subgroups based on their extracellular domains, the Ig-con-. The leucine-rich repeat subgroup consists of at least 10 Toll-like receptors (TLRs) (2, 4 –7), which detect invasion of pathogens by recognizing the pathogen-associated molecular patterns, leading to the activation of innate and adaptive immune responses. Genetic and biochemical studies revealed that IL-1R mediates a very complex pathway, involving a cascade of kinases organized by multiple adapter molecules into sequential signaling complexes, leading to the activation of the transcription factors NFB, activating transcription factor, and AP-1 (8 –10). We have previously shown that kinase-inactive mutant IRAK is still phosphorylated in response to IL-1 stimulation when it is
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