Signal-specific and phosphorylation-dependent RelB degradation: a potential mechanism of NF-κB control

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Abstract
RelB is an unusual member of the Rel/NF-κB family of transcription factors which are involved in oncogenic processes. Due to a relaxed control by the IκBs, the cytosolic NF-κB inhibitors, RelB is constitutively expressed in the nuclei of lymphoid cells. We show here that RelB is inducibly degraded upon activation of T cells in a fashion similar to the IκBs. However, RelB degradation differs from that of IκBs since it is not induced by TNFα but only by T cell receptor or TPA/ionomycin stimulation. Moreover, RelB degradation occurs in three steps: (i) after stimulation RelB is rapidly phosphorylated at amino acids Thr84 and Ser552 followed by (ii) an N-terminal cut and, finally, (iii) the complete degradation in the proteasomes. Since mutation of the two phosphoacceptor sites to non-acceptor sites abolished RelB phosphorylation in vivo and led to the stabilization of the mutated RelBDM, site-specific phosphorylation appears to be a necessary prerequisite for RelB degradation. RelB is a crucial regulator of NF-κB-dependent gene expression. Thus, the signal-induced degradation of RelB should be an important control mechanism of NF-κB activity.