Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

The immediate early transcription factor nuclear factor (I kappa Bs) kappa B (NF-kappa B) is crucially involved in the regulation of numerous physiological or pathophysiological processes such as inflammation and tumourigenesis. Therefore, the control of NF-kappa B activity, which is mainly regulated by signal-induced degradation of cytoplasmic inhibitors of NF-kappa B (I kappa Bs), is of high relevance. One known alternative pathway of NF-kappa B regulation is the stimulus-induced proteasomal degradation of RelB, a component of the NF-kappa B dimer. Here, we identified the serine/threonine protein kinase glycogen synthase kinase-3 beta (GSK-3 beta) as a critical signalling component leading to RelB degradation. In Jurkat leukaemic T cells as well as in primary human T cells, tetradecanoylphorbolacetate/ionomycinand CD3/CD28-induced RelB degradation were impaired by a GSK-3 beta-specific pharmacological inhibitor, an ectopically expressed dominant-negative GSK-3 beta mutant and by small-interfering RNA-mediated silencing of GSK-3 beta expression. Furthermore, a physical interaction between RelB and GSK-3 beta was shown by co-immunoprecipitation, which was already notable in unstimulated cells. Most importantly, as demonstrated by in vitro kinase assays, human RelB is inducibly phosphorylated by GSK-3 beta, indicating a direct substrate-enzyme relationship. The serine residue 552 is a target of GSK-3 beta-mediated phosphorylation in vitro and in vivo. We conclude that GSK-3 beta is a crucial regulator of RelB degradation, stressing the relevant linkage between the NF-kappa B system and GSK-3 beta. Oncogene (2011) 30, 2485-2492; doi:10.1038/onc.2010.580; published online 10 January 2011