THE INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE IS DEGRADED BY PROTEASOMES FOLLOWING ITS PHOSPHORYLATION

Following interleukin (Lt)-1 stimulation, the majority of the cellular interleukin-1 receptor-associated kinase (IRAK) translocates to a dis crete subset of the Type I IL-1 receptor (IL-IRI) in MRC-5 human lung fibroblasts. As the IRAK becomes multiphosphorylated, it is degraded b y proteasomes at a rate comparable to that of the degradation of the p hosphorylated I kappa B alpha protein, Proteasome inhibitors black the degradation of phosphorylated IRAK and correspondingly increase the a mount of IL-1R1 that can be coimmunoprecipitated with IRAK. The nonspe cific kinase inhibitor K-252b blocks IRAK phosphorylation and degradat ion, but does not inhibit IRAK association with She IL-1R1 indicating that translocation of IRAK to the IL-1R1 and its phosphorylation are i ndependent events. The IL-1 specificity of these effects is indicated by the lack of IRAK phosphorylation and degradation by IL-1 in the pre sence of the IL-1 receptor antagonist or by the activation of MRC-B ce lls by tumor necrosis factor alpha. Long term exposure of MRC-5 cells to IL-1 desensitizes the resynthesized I kappa B alpha to IL-1, but no t to tumor necrosis factor alpha stimulation, but no additional effect s an IRAK are seen.