title: UNC-51/ATG1 kinase regulates axonal transport by mediating motor-cargo assembly.
abstract: Axonal transport mediated by microtubule-dependent motors is vital for neuronal function and viability. Selective sets of cargoes, including macromolecules and organelles, are transported long range along axons to specific destinations. Despite intensive studies focusing on the motor machinery, the regulatory mechanisms that control motor-cargo assembly are not well understood. Here we show that UNC-51/ATG1 kinase regulates the interaction between synaptic vesicles and motor complexes during transport in Drosophila. UNC-51 binds UNC-76, a kinesin heavy chain (KHC) adaptor protein. Loss of unc-51 or unc-76 leads to severe axonal transport defects in which synaptic vesicles are segregated from the motor complexes and accumulate along axons. Genetic studies show that unc-51 and unc-76 functionally interact in vivo to regulate axonal transport. UNC-51 phosphorylates UNC-76 on Ser(143), and the phosphorylated UNC-76 binds Synaptotagmin-1, a synaptic vesicle protein, suggesting that motor-cargo interactions are regulated in a phosphorylation-dependent manner. In addition, defective axonal transport in unc-76 mutants is rescued by a phospho-mimetic UNC-76, but not a phospho-defective UNC-76, demonstrating the essential role of UNC-76 Ser(143) phosphorylation in axonal transport. Thus, our data provide insight into axonal transport regulation that depends on the phosphorylation of adaptor proteins.
authors.affiliation: Division of Neurosciences, Beckman Research Institute of the City of Hope, California 91010, USA.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Toda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Rafael
authors.initials: R
authors.lastname: Flores
authors.forename: Rebecca
authors.initials: R
authors.lastname: Josowitz
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Krasieva
authors.forename: Vickie J
authors.initials: VJ
authors.lastname: Lamorte
authors.forename: Emiko
authors.initials: E
authors.lastname: Suzuki
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gindhart
authors.forename: Katsuo
authors.initials: K
authors.lastname: Furukubo-Tokunaga
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D000071189:Autophagy-Related Protein-1 Homolog; D001370:Axonal Transport / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; C484031:UNC-76 protein, Drosophila; C518074:Atg1 protein, Drosophila; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases