title: NUB1 modulation of GSK3β reduces tau aggregation.
abstract: Abnormal phosphorylation of the microtubule-associated protein tau in neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration, is associated with disrupted axonal transport and synaptic dysfunction ultimately manifesting as histopathological lesions of protein aggregates. Glycogen synthase kinase 3β (GSK3β) may be critical for the pathological hyperphosphorylation of tau. Here, we examined the role of the proteasome-associated protein Nedd8 ultimate buster 1 (NUB1) in the neuropathogenic phosphorylation and aggregation of tau. We reveal that NUB1 interacted with both tau and GSK3β to disrupt their interaction, and abolished recruitment of GSK3β to tau inclusions. Moreover, NUB1 reduced GSK3β-mediated phosphorylation of tau and aggregation of tau in intracellular inclusions. Strikingly, NUB1 induced GSK3β degradation. Deletion of the NUB1 ubiquitin-like (UBL) domain did not impair the interaction with tau and GSK3β, and the ability to suppress the phosphorylation and aggregation of tau was not affected. However, the UBL motif was necessary for GSK3β degradation. Deletion of the NUB1 ubiquitin-associated (UBA) domain abrogated the ability of NUB1 to interact with and degrade GSK3β. Moreover, the UBA domain was required to suppress the aggregation of tau. Silencing of NUB1 in cells stabilized endogenous GSK3β and exacerbated tau phosphorylation. Thus, we propose that NUB1, by regulating GSK3β levels, modulates tau phosphorylation and aggregation, and is a key player in neurodegeneration associated with tau pathology. Moreover, NUB1 regulation of GSK3β could modulate numerous signalling pathways in which GSK3β is a centrally important effector.
authors.affiliation: UCL Institute of Ophthalmology, London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Richet
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.forename: Teresa
authors.initials: T
authors.lastname: Rodriguez
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Novoselov
authors.forename: Gunter
authors.initials: G
authors.lastname: Schmidtke
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van der Spuy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3