The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation.
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.
Yamin
T T
TT
Department of Inflammation Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Miller
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DK
D001692:Biological Transport; D002227:Carbazoles / Q000494:pharmacology; D002451:Cell Compartmentation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D026121:Indole Alkaloids; D053592:Interleukin-1 Receptor-Associated Kinases; D009097:Multienzyme Complexes / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002227:Carbazoles; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D026121:Indole Alkaloids; D009097:Multienzyme Complexes; C000606204:NFKBIA protein, human; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C049985:staurosporine aglycone; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex