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

Abstract

The immediate early transcription factor nuclear factor (IκBs) kappa B (NF-κB) is crucially involved in the regulation of numerous physiological or pathophysiological processes such as inflammation and tumourigenesis. Therefore, the control of NF-κB activity, which is mainly regulated by signal-induced degradation of cytoplasmic inhibitors of NF-κB (IκBs), is of high relevance. One known alternative pathway of NF-κB regulation is the stimulus-induced proteasomal degradation of RelB, a component of the NF-κB dimer. Here, we identified the serine/threonine protein kinase glycogen synthase kinase-3β (GSK-3β) as a critical signalling component leading to RelB degradation. In Jurkat leukaemic T cells as well as in primary human T cells, tetradecanoylphorbolacetate/ionomycin- and CD3/CD28-induced RelB degradation were impaired by a GSK-3β-specific pharmacological inhibitor, an ectopically expressed dominant-negative GSK-3β mutant and by small-interfering RNA-mediated silencing of GSK-3β expression. Furthermore, a physical interaction between RelB and GSK-3β 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-3β, indicating a direct substrate–enzyme relationship. The serine residue 552 is a target of GSK-3β-mediated phosphorylation in vitro and in vivo. We conclude that GSK-3β is a crucial regulator of RelB degradation, stressing the relevant linkage between the NF-κB system and GSK-3β.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (NE608/3-2 to MN; LE953/5-1 to ML) and by DFG grant SFB-TR19 (to KK and RK). We thank Sandra Bundschuh, Beatrix Kramer and Konstantin Klein for their excellent technical assistance.

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Correspondence to M Neumann.

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Neumann, M., Klar, S., Wilisch-Neumann, A. et al. Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation. Oncogene 30, 2485–2492 (2011). https://doi.org/10.1038/onc.2010.580

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