Immunosuppressant FK506 activates NF-κB through the proteasome-mediated degradation of IκBα -: Requirement for IκBα N-terminal phosphorylation but not ubiquitination sites

The immunosuppressant FK506 activates NJ-kappa B through I kappa B alpha degradation in nonlymphoid cells. In the present study, we analyzed mechanisms by which FK506 induces I kappa B alpha degradation. We found that FK506 induces the degradation of both I kappa B alpha and I kappa B beta and that the time courses of the FK506-induced degradation are quite different from degradation induced by interleukin 1 (IL-1). Despite this difference, FK506-induced I kappa B alpha degradation was dependent on the N-terminal Ser-32 and Ser-36 phosphorylation sites and was mediated by proteasomes, as is the case for IL-1-induced I kappa B alpha degradation. We further showed that FK506 induces weak and slow phosphorylation of I kappa B alpha at Ser-32. However, unlike IL-1-induced degradation, IKK-1 and IKK-2 were not activated significantly nor was FK506-induced I kappa B alpha degradation dependent on the N-terminal ubiquitination sites (Lys-21 and Lys-22). These results therefore indicate that FK506 and IL-1 utilize similar but distinct mechanisms to induce the phosphorylation and degradation of I kappa B alpha.