title: KIS, a kinase associated with microtubule regulators, enhances translation of AMPA receptors and stimulates dendritic spine remodeling.
abstract: Local regulation of protein synthesis allows a neuron to rapidly alter the proteome in response to synaptic signals, an essential mechanism in synaptic plasticity that is altered in many neurological diseases. Synthesis of many synaptic proteins is under local control and much of this regulation occurs through structures termed RNA granules. KIS is a protein kinase that associates with stathmin, a modulator of the tubulin cytoskeleton. Furthermore, KIS is found in RNA granules and stimulates translation driven by the β-actin 3'UTR in neurites. Here we explore the physiological and molecular mechanisms underlying the action of KIS on hippocampal synaptic plasticity in mice. KIS downregulation compromises spine development, alters actin dynamics, and reduces postsynaptic responsiveness. The absence of KIS results in a significant decrease of protein levels of PSD-95, a postsynaptic scaffolding protein, and the AMPAR subunits GluR1 and GluR2 in a CPEB3-dependent manner. Underlying its role in spine maturation, KIS is able to suppress the spine developmental defects caused by CPEB3 overexpression. Moreover, either by direct or indirect mechanisms, KIS counteracts the inhibitory activity of CPEB3 on the GluR2 3'UTR at both mRNA translation and polyadenylation levels. Our study provides insights into the mechanisms that mediate dendritic spine morphogenesis and functional synaptic maturation, and suggests KIS as a link regulating spine cytoskeleton and postsynaptic activity in memory formation.
authors.affiliation: Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain and.
authors.forename: Neus
authors.identifier: http://orcid.org/0000-0003-4749-5111
authors.initials: N
authors.lastname: Pedraza
authors.affiliation: Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain and.
authors.forename: Raúl
authors.identifier: http://orcid.org/0000-0003-2040-2093
authors.initials: R
authors.lastname: Ortiz
authors.affiliation: Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain and.
authors.forename: Alba
authors.initials: A
authors.lastname: Cornadó
authors.affiliation: Laboratory of Neurobiology, Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain.
authors.forename: Artur
authors.identifier: http://orcid.org/0000-0001-5797-6782
authors.initials: A
authors.lastname: Llobet
authors.affiliation: Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain and.
authors.forename: Martí
authors.initials: M
authors.lastname: Aldea
authors.affiliation: Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain and cggbmc@ibmb.csic.es.
authors.forename: Carme
authors.identifier: http://orcid.org/0000-0001-6961-3524
authors.initials: C
authors.lastname: Gallego
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008870:Microtubules / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D009924:Organ Culture Techniques; D014176:Protein Biosynthesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D018091:Receptors, AMPA / Q000096:biosynthesis*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018091:Receptors, AMPA; D017346:Protein Serine-Threonine Kinases; C530659:Uhmk1 protein, mouse
keywords: AMPA receptors; KIS; hippocampus; local translation; spine remodeling; synaptic plasticity