GSK-3? controls NF-kappaB activity via IKK?/NEMO.

ABSTRACT: The NF-?B 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. IKK?/NEMO is essential for NF-?B 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-3? (GSK-3?) participates in NF-?B regulation but the exact mechanism remained incompletely understood. In this study, we identified NEMO as a GSK-3? 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-3? binding and subsequent phosphorylation of NEMO resulting in its destabilization. However, K63-linked polyubiquitination was augmented in mutated NEMO explaining an increased binding to IKK? and IKK?. Even I?B? was found degraded. Still, TNF?-stimulated NF-?B activation was impaired pointing towards an un-controlled signalling process. Our data suggest that GSK-3? is critically important for ordered NF-?B signalling through modulation of NEMO phosphorylation.

SUBMITTER: Medunjanin S 

PROVIDER: S-EPMC5144080 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other