title: Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylation-dependent mechanism.
abstract: Proper regulation of microtubule dynamics is essential for cell functions and involves various microtubule-associated proteins (MAPs). Among them, end-binding proteins (EBs) accumulate at microtubule plus ends, whereas structural MAPs bind along the microtubule lattice. Recent data indicate that the structural MAP tau modulates EB subcellular localization in neurons. However, the molecular determinants of EB/tau interaction remain unknown, as is the effect of this interplay on microtubule dynamics. Here we investigate the mechanisms governing EB/tau interaction in cell-free systems and cellular models. We find that tau inhibits EB tracking at microtubule ends. Tau and EBs form a complex via the C-terminal region of EBs and the microtubule-binding sites of tau. These two domains are required for the inhibitory activity of tau on EB localization to microtubule ends. Moreover, the phosphomimetic mutation S262E within tau microtubule-binding sites impairs EB/tau interaction and prevents the inhibitory effect of tau on EB comets. We further show that microtubule dynamic parameters vary, depending on the combined activities of EBs and tau proteins. Overall our results demonstrate that tau directly antagonizes EB function through a phosphorylation-dependent mechanism. This study highlights a novel role for tau in EB regulation, which might be impaired in neurodegenerative disorders.
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France.
authors.forename: Sacnicte
authors.initials: S
authors.lastname: Ramirez-Rios
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France CEA, BIG-GPC, F-38000 Grenoble France.
authors.forename: Eric
authors.initials: E
authors.lastname: Denarier
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France.
authors.forename: Eléa
authors.initials: E
authors.lastname: Prezel
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Vinit
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Stoppin-Mellet
authors.affiliation: Aix-Marseille Université, INSERM, CRO2 UMR_S 911, Faculté de Pharmacie, F-13385 Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Devred
authors.affiliation: Aix-Marseille Université, INSERM, CRO2 UMR_S 911, Faculté de Pharmacie, F-13385 Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Barbier
authors.affiliation: Aix-Marseille Université, INSERM, CRO2 UMR_S 911, Faculté de Pharmacie, F-13385 Marseille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
authors.affiliation: Centro de Investigaciones Biomédicas de Canarias entro de Investigaciones Biomédicas de Canarias, Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38071 Tenerife, Spain.
authors.forename: Carmen Laura
authors.initials: CL
authors.lastname: Sayas
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28029 Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Avila
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France.
authors.forename: Leticia
authors.initials: L
authors.lastname: Peris
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France CEA, BIG-GPC, F-38000 Grenoble France.
authors.forename: Annie
authors.initials: A
authors.lastname: Andrieux
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Serre
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France CEA, BIG-GPC, F-38000 Grenoble France.
authors.forename: Anne
authors.initials: A
authors.lastname: Fourest-Lieuvin
authors.affiliation: Université Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France INSERM, U1216, F-38000 Grenoble, France isabelle.arnal@univ-grenoble-alpes.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnal
mesh_terms: D002474:Cell-Free System / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D021381:Protein Transport; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C500985:MAPRE1 protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins