title: 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.
authors.affiliation: Department of Molecular Pathology, Institute for Pathology, University Hospital, Eberhard Karls University, Tuebingen, Germany. manfred.neumann@med.uni-tuebingen.de
authors.forename: M
authors.initials: M
authors.lastname: Neumann
authors.forename: S
authors.initials: S
authors.lastname: Klar
authors.forename: A
authors.initials: A
authors.lastname: Wilisch-Neumann
authors.forename: E
authors.initials: E
authors.lastname: Hollenbach
authors.forename: S
authors.initials: S
authors.lastname: Kavuri
authors.forename: M
authors.initials: M
authors.lastname: Leverkus
authors.forename: R
authors.initials: R
authors.lastname: Kandolf
authors.forename: M C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
authors.forename: K
authors.initials: K
authors.lastname: Klingel
mesh_terms: D002227:Carbazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D008301:Maleimides / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D013379:Substrate Specificity; D051841:Transcription Factor RelB / Q000378:metabolism*
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011758:Pyrroles; C497593:RELB protein, human; C417521:SB 216763; C081021:Go 6976; D051841:Transcription Factor RelB; C085989:Ro 32-0432; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3