Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport

Abstract

AbstractKinesin-1 undergoes autoinhibition but its functional significance has been unclear. Kinesin-1 transports multiple cargoes including cytoplasmic dynein to the microtubule plus ends. From a genetic screen for Aspergills mutants defective in dynein-mediated early endosome transport, we identified a kinesin-1 mutation kinAK895* that disrupts kinesin-1 autoinhibition. Consistent with kinAK895* making kinesin-1 constitutively active, the mutant proteins accumulate abnormally near the microtubule plus ends. Unexpectedly, our genetic data show that kinesin-1 autoinhibition is unnecessary for transporting its cargoes such as secretory vesicles. Dynein accumulates normally at the microtubule plus ends in the kinAK895* mutant. However, the frequency but not the speed of dynein-mediated early endosome transport is significantly decreased, indicating that kinesin-1 autoinhibition facilitates dynein to initiate its cargo transport. Furthermore, kinesin-1 autoinhibition promotes dynein cargo initiation in a way mechanistically distinct from LIS1-promoted dynein switching from its autoinhibited form. Thus, while dynein activation involves dynactin, cargo adapter and LIS1, this study adds kinesin-1 autoinhibition as a new regulatory factor in vivo.