GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Sci Rep. 2016 Dec 8;6:38553. doi: 10.1038/srep38553.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / metabolism
  • MCF-7 Cells
  • Mice
  • Mutant Proteins / metabolism
  • NF-kappa B / metabolism*
  • NIH 3T3 Cells
  • Phosphorylation
  • Protein Binding
  • Protein Stability

Substances

  • IKBKG protein, human
  • Mutant Proteins
  • NF-kappa B
  • Glycogen Synthase Kinase 3 beta
  • I-kappa B Kinase