title: KIBRA (KIdney/BRAin protein) regulates learning and memory and stabilizes Protein kinase Mζ.
abstract: The WWC1 gene has been genetically associated with human episodic memory performance, and its product KIdney/BRAin protein (KIBRA) has been shown to interact with the atypical protein kinase protein kinase M ζ (PKMζ). Although recently challenged, PKMζ remains a candidate postsynaptic regulator of memory maintenance. Here, we show that PKMζ is subject to rapid proteasomal degradation and that KIBRA is both necessary and sufficient to counteract this process, thus stabilizing the kinase and maintaining its function for a prolonged time. We define the binding sequence on KIBRA, a short amino acid motif near the C-terminus. Both hippocampal knock-down of KIBRA in rats and KIBRA knock-out in mice result in decreased learning and memory performance in spatial memory tasks supporting the notion that KIBRA is a player in episodic memory. Interestingly, decreased memory performance is accompanied by decreased PKMζ protein levels. We speculate that the stabilization of synaptic PKMζ protein levels by KIBRA may be one mechanism by which KIBRA acts in memory maintenance. KIBRA/WWC1 has been genetically associated with human episodic memory. KIBRA has been shown to be post-synaptically localized, but its function remained obscure. Here, we show that KIBRA shields PKMζ, a kinase previously linked to memory maintenance, from proteasomal degradation via direct interaction. KIBRA levels in the rodent hippocampus correlate closely both to spatial memory performance in rodents and to PKMζ levels. Our findings support a role for KIBRA in memory, and unveil a novel function for this protein.
authors.affiliation: SYGNIS Bioscience, Heidelberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Vogt-Eisele
authors.forename: Carola
authors.initials: C
authors.lastname: Krüger
authors.forename: Kerstin
authors.initials: K
authors.lastname: Duning
authors.forename: Daniela
authors.initials: D
authors.lastname: Weber
authors.forename: Robert
authors.initials: R
authors.lastname: Spoelgen
authors.forename: Claudia
authors.initials: C
authors.lastname: Pitzer
authors.forename: Christian
authors.initials: C
authors.lastname: Plaas
authors.forename: Gisela
authors.initials: G
authors.lastname: Eisenhardt
authors.forename: Annette
authors.initials: A
authors.lastname: Meyer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Vogt
authors.forename: Markus
authors.initials: M
authors.lastname: Krieger
authors.forename: Eva
authors.initials: E
authors.lastname: Handwerker
authors.forename: Dirk Oliver
authors.initials: DO
authors.lastname: Wennmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Weide
authors.forename: Boris V
authors.initials: BV
authors.lastname: Skryabin
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Kremerskothen
authors.forename: Armin
authors.initials: A
authors.lastname: Schneider
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D056970:Co-Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D005816:Genetic Complementation Test; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D007858:Learning / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010750:Phosphoproteins; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013238:Stereotaxic Techniques; D000099221:Protein Kinase C zeta
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C539495:Wwc1 protein, mouse; C504730:protein kinase M zeta, rat
keywords: degradation; hippocampus; kinase; memory; proteasome; ubiquitin