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

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Abstract

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.

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Abbreviations

AMPPNP:

5′-Adenylylimidodiphosphate

BDNF:

Brain-derived neurotrophic factor

CO-IP:

Co-immunoprecipitation

CT:

C-terminus

DRG:

Dorsal root ganglia

IL2R:

Interleukin-2 receptor

JIP:

JNK-interacting protein

JM:

Juxtamembrane

JNK:

c-Jun NH2-terminal kinase

KHC:

Kinesin-1 heavy chain

KLC:

Kinesin-1 light chain

TK:

Tyrosine kinase

TrkB:

Tropomyosin receptor kinase B

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 31401219, 31130026 and 91432306), Shandong Provincial Natural Science Foundation, China (No. ZR2014CQ023), China Postdoctoral Science Foundation Funded Project (Nos. 2014M551896 and 2015T80708), the National 973 Basic Research Program of China (No. 2012CB911000), the State Program of National Natural Science Foundation of China for Innovative Research Group (No. 81321061) and the Foundation for Excellent Young Scientist of Shandong Province (No. BS2015SW005).

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Authors and Affiliations

  1. Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, People’s Republic of China

    Tao Sun & Ming Hou

  2. Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Collaborative Innovation Center for Brain Science, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China

    Tao Sun, Yuan Li, Ting Li, Huixian Ma, Yunyun Guo, Shuhong Huang & Zheyu Chen

  3. Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100190, People’s Republic of China

    Xingyu Jiang

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Correspondence to Shuhong Huang or Zheyu Chen.

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Sun, T., Li, Y., Li, T. et al. JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1. Cell. Mol. Life Sci. 74, 4027–4044 (2017). https://doi.org/10.1007/s00018-017-2568-z

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