JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1.

Long-range anterograde axonal transport of TrkB is important for neurons to exert appropriate BDNF responses. TrkB anterograde axonal delivery is mediated by kinesin-1, which associates with TrkB via the adaptor protein JIP3 or the Slp1/Rab27B/CRMP-2 protein complex. However, little is known about the activation mechanisms of TrkB-loaded kinesin-1. Here, we show that JIP1 mediates TrkB anterograde axonal transport using JIP1 knockout mice, sciatic nerve ligation analysis and live imaging. Next, we proved that JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport. Finally, microtubule-binding and microfluidic chamber assays revealed that JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition, which depends on the binding of JIP1 to kinesin-1 heavy chain (KHC) and light chain (KLC) and the binding of JIP3 to KLC and is essential for TrkB anterograde axonal transport and BDNF-induced TrkB retrograde signal. These findings could deepen our understanding of the regulation mechanism underlying TrkB anterograde axonal transport and provide a novel kinesin-1 autoinhibition-relieving model.