UNC-51/ATG1 kinase regulates axonal transport by mediating motor–cargo assembly |
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Authors: | Hirofumi Toda Hiroaki Mochizuki Rafael Flores III Rebecca Josowitz Tatiana B. Krasieva Vickie J. LaMorte Emiko Suzuki Joseph G. Gindhart Katsuo Furukubo-Tokunaga Toshifumi Tomoda |
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Affiliation: | 1. Division of Neurosciences, Beckman Research Institute of the City of Hope, California 91010, USA;;2. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan;;3. Department of Biology, University of Richmond, Virginia 23173, USA;;4. Beckman Laser Institute, University of California at Irvine, Irvine, California 92697, USA;;5. Gene Network Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan |
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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 Ser143, 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 Ser143 phosphorylation in axonal transport. Thus, our data provide insight into axonal transport regulation that depends on the phosphorylation of adaptor proteins. |
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Keywords: | Axonal transport unc-51 kinesin adaptor phosphorylation motor–cargo assembly |
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