Regulation of Axonal Transport by Kinesin Phosphorylation at S176

Abstract

The means by which the neuron regulates axonal transport of cargo remains an open field for study. Recent experiments examining Huntington's disease (HD) have revealed a molecular basis underlying fast axonal transport deficits characteristic of HD. This mechanism involves activation of JNK3 and JNK3-mediated phosphorylation of the kinesin-1 heavy chain (KHC) at serine 176. We have generated a phosphomimetic KHC construct (S176D) to characterize the effects phosphorylation has on kinesin's ability to translocate along microtubules. Using total internal reflection florescence (TIRF) microscopy, we have measured a dramatic reduction in the processive run length of S176D, as compared to the unphosphorylatable variant S176A. While this observation reveals a mechanism by which neurons control anterograde trafficking, it also suggests a mechanism for tuning the bidirectional transport of vesicles by kinesin and dynein.