title: GSK-3β controls NF-kappaB activity via IKKγ/NEMO.
abstract: The NF-κB signaling pathway is central for the innate immune response and its deregulation is found in multiple disorders such as autoimmune, chronic inflammatory and metabolic diseases. IKKγ/NEMO is essential for NF-κB activation and NEMO dysfunction in humans has been linked to so-called progeria syndromes, which are characterized by advanced ageing due to age-dependent inflammatory diseases. It has been suggested that glycogen synthase kinase-3β (GSK-3β) participates in NF-κB regulation but the exact mechanism remained incompletely understood. In this study, we identified NEMO as a GSK-3β substrate that is phosphorylated at serine 8, 17, 31 and 43 located within its N-terminal domain. The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3β binding and subsequent phosphorylation of NEMO resulting in its destabilization. However, K63-linked polyubiquitination was augmented in mutated NEMO explaining an increased binding to IKKα and IKKβ. Even IκBα was found degraded. Still, TNFα-stimulated NF-κB activation was impaired pointing towards an un-controlled signalling process. Our data suggest that GSK-3β is critically important for ordered NF-κB signalling through modulation of NEMO phosphorylation.
authors.affiliation: Internal Medicine/Cardiology and Angiology, Magdeburg University, Magdeburg, Germany.
authors.forename: Senad
authors.initials: S
authors.lastname: Medunjanin
authors.affiliation: Internal Medicine/Cardiology and Angiology, Magdeburg University, Magdeburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schleithoff
authors.affiliation: Internal Medicine/Cardiology and Angiology, Magdeburg University, Magdeburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Fiegehenn
authors.affiliation: Internal Medicine/Cardiology and Angiology, Magdeburg University, Magdeburg, Germany.
authors.forename: Soenke
authors.initials: S
authors.lastname: Weinert
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Zuschratter
authors.affiliation: Internal Medicine/Cardiology and Angiology, Magdeburg University, Magdeburg, Germany.
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
mesh_terms: D000818:Animals; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D055550:Protein Stability
chemical_list: C491731:IKBKG protein, human; D050505:Mutant Proteins; D016328:NF-kappa B; D000071679:Glycogen Synthase Kinase 3 beta; D051550:I-kappa B Kinase