title: Casein kinase 1 controls the activation threshold of an α-arrestin by multisite phosphorylation of the interdomain hinge.
abstract: α-Arrestins play a key role as trafficking adaptors in both yeast and mammals. The yeast Rim8/Art9 α-arrestin mediates the recruitment of endosomal sorting complex required for transport (ESCRT) to the seven-transmembrane protein Rim21 in the ambient pH signaling RIM pathway. ESCRT is believed to function as a signaling platform that enables the proteolytic activation of the Rim101 transcription factor upon external alkalization. Here we provide evidence that the pH signal promotes the stable association of Rim8 with Rim21 at the plasma membrane. We show that Rim8 is phosphorylated in a pH-independent but Rim21-dependent manner by the plasma membrane-associated casein kinase 1 (CK1). We further show that this process involves a cascade of phosphorylation events within the hinge region connecting the arrestin domains. Strikingly, loss of casein kinase 1 activity causes constitutive activation of the RIM pathway, and, accordingly, pH signaling is activated in a phosphodeficient Rim8 mutant and impaired in the corresponding phosphomimetic mutant. Our results indicate that Rim8 phosphorylation prevents its accumulation at the plasma membrane at acidic pH and thereby inhibits RIM signaling. These findings support a model in which CK1-mediated phosphorylation of Rim8 contributes to setting a signaling threshold required to inhibit the RIM pathway at acidic pH.
authors: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors: Antonio
authors: A
authors: Herrador
authors: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors: Daniela
authors: D
authors: Livas
authors: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors: Lucía
authors: L
authors: Soletto
authors: Institut Jacques Monod, Centre National de la Recherche Scientifique, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France.
authors: Michel
authors: M
authors: Becuwe
authors: Institut Jacques Monod, Centre National de la Recherche Scientifique, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France.
authors: Sébastien
authors: S
authors: Léon
authors: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain ovincent@iib.uam.es.
authors: Olivier
authors: O
authors: Vincent
mesh_terms: D047389:Casein Kinase I / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002462:Cell Membrane / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; C547025:Rim21 protein, S cerevisiae; C547024:Rim8 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D047389:Casein Kinase I