Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons.
The transport of vesicles in neurons is a highly regulated process, with vesicles moving either anterogradely or retrogradely depending on the nature of the molecular motors, kinesins and dynein, respectively, which propel vesicles along microtubules (MTs). However, the mechanisms that determine the directionality of transport remain unclear. Huntingtin, the protein mutated in Huntington's disease, is a positive regulatory factor for vesicular transport. Huntingtin is phosphorylated at serine 421 by the kinase Akt but the role of this modification is unknown. Here, we demonstrate that phosphorylation of wild-type huntingtin at S421 is crucial to control the direction of vesicles in neurons. When phosphorylated, huntingtin recruits kinesin-1 to the dynactin complex on vesicles and MTs. Using brain-derived neurotrophic factor as a marker of vesicular transport, we demonstrate that huntingtin phosphorylation promotes anterograde transport. Conversely, when huntingtin is not phosphorylated, kinesin-1 detaches and vesicles are more likely to undergo retrograde transport. This also applies to other vesicles suggesting an essential role for huntingtin in the control of vesicular directionality in neurons.
Colin
Emilie
E
Institut Curie, Orsay, France.
Zala
Diana
D
Liot
Géraldine
G
Rangone
Hélène
H
Borrell-Pagès
Maria
M
Li
Xiao-Jiang
XJ
Saudou
Frédéric
F
Humbert
Sandrine
S
D000818:Animals; D001693:Biological Transport, Active; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D000072159:Dynactin Complex; D006801:Humans; D000071058:Huntingtin Protein; D016547:Kinesins / Q000502:physiology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000502:physiology; D008870:Microtubules / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D033921:Vesicular Transport Proteins / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D000072159:Dynactin Complex; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D033921:Vesicular Transport Proteins; D016547:Kinesins