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: Josta T Kevenaar, Sarah Bianchi, Myrrhe van Spronsen, Natacha Olieric, Joanna Lipka, Cátia P Frias, Marina Mikhaylova, Martin Harterink, Nanda Keijzer, Phebe S Wulf, Manuel Hilbert, Lukas C Kapitein, Esther de Graaff, Anna Ahkmanova, Michel O Steinmetz, Casper C Hoogenraad
• Journal: Current biology : CB (Curr Biol) Vol. 26 Issue 7 Pg. 849-61 (Apr 04 2016) ISSN: 1879-0445 [Electronic] England
• PMID: 26948876 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Carrier Proteins
• KBP protein, mouse
• KIF1A protein, human
• KIFBP protein, human
• Nerve Tissue Proteins
• Kinesins

Topics

• Animals
• Caenorhabditis elegans (metabolism)
• Carrier Proteins (metabolism)
• Craniofacial Abnormalities (metabolism)
• Hirschsprung Disease (metabolism)
• Kinesins (chemistry, metabolism)
• Mice
• Microtubules (metabolism)
• Nerve Tissue Proteins (metabolism)
• Neurons (metabolism)
• Synaptic Vesicles (metabolism)