The Interleukin-1 Receptor-associated Kinase Is Degraded by Proteasomes following Its Phosphorylation

Ting-Ting Yamin,Douglas K Miller

doi:10.1074/jbc.272.34.21540

Abstract

Following interleukin (IL)-1 stimulation, the majority of the cellular interleukin-1 receptor-associated kinase (IRAK) translocates to a discrete subset of the Type I IL-1 receptor (IL-1R1) in MRC-5 human lung fibroblasts. As the IRAK becomes multiphosphorylated, it is degraded by proteasomes at a rate comparable to that of the degradation of the phosphorylated IkappaBalpha protein. Proteasome inhibitors block the degradation of phosphorylated IRAK and correspondingly increase the amount of IL-1R1 that can be coimmunoprecipitated with IRAK. The nonspecific kinase inhibitor K-252b blocks IRAK phosphorylation and degradation, but does not inhibit IRAK association with the IL-1R1 indicating that translocation of IRAK to the IL-1R1 and its phosphorylation are independent events. The IL-1 specificity of these effects is indicated by the lack of IRAK phosphorylation and degradation by IL-1 in the presence of the IL-1 receptor antagonist or by the activation of MRC-5 cells by tumor necrosis factor alpha. Long term exposure of MRC-5 cells to IL-1 desensitizes the resynthesized IkappaBalpha to IL-1, but not to tumor necrosis factor alpha stimulation, but no additional effects on IRAK are seen.

Highlights

IL-11 is a master cytokine responsible for the induction of a number of proteins associated with inflammation, such as metalloproteinases, cyclooxygenase, nitric-oxide synthetase, and adhesion proteins [1]
When the MRC-5 cells were activated with IL-1␣, this sharp IL-1 receptor-associated kinase (IRAK) band disappeared and a diffuse higher molecular weight band was formed as detected with the I700 –712 antisera (Fig. 1B), analogous to the migration of the phosphorylated IRAK reported earlier [5]
In the present report we confirm in a normal human fibroblast line the previous observations in IL-1R1-transfected HEK cells that IRAK associates with the IL-1R1 and becomes phosphorylated after IL-1 stimulation [5]

Summary

Introduction

IL-11 is a master cytokine responsible for the induction of a number of proteins associated with inflammation, such as metalloproteinases, cyclooxygenase, nitric-oxide synthetase, and adhesion proteins [1]. In contrast to the rapid disappearance of IRAK following IL-1 activation, the MRC-5 cell IL-1R1 is neither phosphorylated nor diminished in total amount (data not shown).

Results

Conclusion