Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway.
Axonal transport of mitochondria and synaptic vesicle precursors via kinesin motor proteins is essential to keep integrity of axons and synapses. Disturbance of axonal transport is an early sign of neuroinflammatory and neurodegenerative diseases. Treatment of cultured neurons by the inflammatory cytokine tumor necrosis factor-alpha (TNF) stimulated phosphorylation of c-Jun N-terminal kinase (JNK) in neurites. TNF treatment induced dissociation of the heavy chain kinesin family-5B (KIF5B) protein from tubulin in axons but not cell bodies as determined by lifetime-based Förster resonance energy transfer (FRET) analysis. Dissociation of KIF5B from tubulin after TNF treatment was dependent on JNK activity. Furthermore, TNF inhibited axonal transport of mitochondria and synaptophysin by reducing the mobile fraction via JNK. Thus, TNF produced by activated glial cells in inflammatory or degenerative neurological diseases acts on neurites by acting on the kinesin-tubulin complex and inhibits axonal mitochondria and synaptophysin transport via JNK.
Stagi
Massimiliano
M
Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn Life and Brain Center, University Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Gorlovoy
Philipp
P
Larionov
Sergey
S
Takahashi
Kazuya
K
Neumann
Harald
H
D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D007249:Inflammation / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016547:Kinesins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D016708:Synaptophysin / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
D016708:Synaptophysin; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; C475469:Kif5b protein, mouse; D016547:Kinesins