-TrCP-Mediated IRAK1 Degradation Releases TAK1-TRAF6 from the Membrane to the Cytosol for TAK1-Dependent NF-B Activation

proteins have been shown to meditate K63-linked polyubiquitination on IRAK1, the E3 ligase for K48-linked ubiquitination of IRAK1 has not been identified. In this study, we report that the SCF (Skp1–Cullin1–F-box)–-TrCP complex functions as the K48-linked ubiquitination E3 ligase for IRAK1. IL-1 stimulation induced the interaction of IRAK1 with Cullin1 and -TrCP. Knockdown of-TrCP1 and-TrCP2 attenuated the K48-linked ubiquitination and degradation of IRAK1. Importantly, -TrCP deficiency abolished the translocation TAK1-TRAF6 complex from the membrane to the cytosol, resulting in a dimin-ishment of the IL-1-induced TAK1-dependent pathway. Taken together, these results implicate a positive role of -TrCP-medi-ated IRAK1 degradation in IL-1-induced TAK1 activation. Interleukin-1 (IL-1), a major proinflammatory cytokine, has awide range of pathophysiological functions in autoimmune and inflammatory responses. Genetic and biochemical studies re-vealed that IL-1 receptor (IL-1R)-mediated signaling involves a cascade of kinases organized by multiple adapter molecules into signaling complexes, leading to activation of the transcription fac-tor NF-B. Based on studies by our group and others, we postu-lated a model for the IL-1 pathway (4, 6, 8–10, 14, 22). Upon IL-1 stimulation, the IL-1 receptor recruits the adaptor molecul