title: Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity.
abstract: Kinesin motor proteins play a fundamental role for normal neuronal development by controlling intracellular cargo transport and microtubule (MT) cytoskeleton organization. Regulating kinesin activity is important to ensure their proper functioning, and their misregulation often leads to severe human neurological disorders. Homozygous nonsense mutations in kinesin-binding protein (KBP)/KIAA1279 cause the neurological disorder Goldberg-Shprintzen syndrome (GOSHS), which is characterized by intellectual disability, microcephaly, and axonal neuropathy. Here, we show that KBP regulates kinesin activity by interacting with the motor domains of a specific subset of kinesins to prevent their association with the MT cytoskeleton. The KBP-interacting kinesins include cargo-transporting motors such as kinesin-3/KIF1A and MT-depolymerizing motor kinesin-8/KIF18A. We found that KBP blocks KIF1A/UNC-104-mediated synaptic vesicle transport in cultured hippocampal neurons and in C. elegans PVD sensory neurons. In contrast, depletion of KBP results in the accumulation of KIF1A motors and synaptic vesicles in the axonal growth cone. We also show that KBP regulates neuronal MT dynamics by controlling KIF18A activity. Our data suggest that KBP functions as a kinesin inhibitor that modulates MT-based cargo motility and depolymerizing activity of a subset of kinesin motors. We propose that misregulation of KBP-controlled kinesin motors may represent the underlying molecular mechanism that contributes to the neuropathological defects observed in GOSHS patients.
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands.
authors.forename: Josta T
authors.initials: JT
authors.lastname: Kevenaar
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Myrrhe
authors.initials: M
authors.lastname: van Spronsen
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
authors.forename: Natacha
authors.initials: N
authors.lastname: Olieric
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands; International Institute of Molecular and Cell Biology, 02-1009 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lipka
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands.
authors.forename: Cátia P
authors.initials: CP
authors.lastname: Frias
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands; RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118 Magdeburg, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Mikhaylova
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Harterink
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Nanda
authors.initials: N
authors.lastname: Keijzer
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Phebe S
authors.initials: PS
authors.lastname: Wulf
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hilbert
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Kapitein
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: de Graaff
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Ahkmanova
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 Utrecht, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3015 Rotterdam, the Netherlands. Electronic address: c.hoogenraad@uu.nl.
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000378:metabolism*; D006627:Hirschsprung Disease / Q000378:metabolism*; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C554342:KBP protein, mouse; C094065:KIF1A protein, human; C503132:KIFBP protein, human; D009419:Nerve Tissue Proteins; D016547:Kinesins
keywords: KIF1; KIF13; KIF14; KIF15; KIF18; KIF3; kinesin; microtubule dynamics; neuron; synaptic vesicle; trafficking; transport