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JIP3 Activates Kinesin-1 Motility to Promote Axon Elongation.

ABSTRACT: Kinesin-1 is a molecular motor responsible for cargo transport along microtubules and plays critical roles in polarized cells, such as neurons. Kinesin-1 can function as a dimer of two kinesin heavy chains (KHC), which harbor the motor domain, or as a tetramer in combination with two accessory light chains (KLC). To ensure proper cargo distribution, kinesin-1 activity is precisely regulated. Both KLC and KHC subunits bind cargoes or regulatory proteins to engage the motor for movement along microtubules. We previously showed that the scaffolding protein JIP3 interacts directly with KHC in addition to its interaction with KLC and positively regulates dimeric KHC motility. Here we determined the stoichiometry of JIP3-KHC complexes and observed approximately four JIP3 molecules binding per KHC dimer. We then determined whether JIP3 activates tetrameric kinesin-1 motility. Using an in vitro motility assay, we show that JIP3 binding to KLC engages kinesin-1 with microtubules and that JIP3 binding to KHC promotes kinesin-1 motility along microtubules. We tested the in vivo relevance of these findings using axon elongation as a model for kinesin-1-dependent cellular function. We demonstrate that JIP3 binding to KHC, but not KLC, is essential for axon elongation in hippocampal neurons as well as axon regeneration in sensory neurons. These findings reveal that JIP3 regulation of kinesin-1 motility is critical for axon elongation and regeneration.

SUBMITTER: Watt D

PROVIDER: S-EPMC4505465 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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JIP3 Activates Kinesin-1 Motility to Promote Axon Elongation.

Watt Dana D Dixit Ram R Cavalli Valeria V

The Journal of biological chemistry 20150505 25

Kinesin-1 is a molecular motor responsible for cargo transport along microtubules and plays critical roles in polarized cells, such as neurons. Kinesin-1 can function as a dimer of two kinesin heavy chains (KHC), which harbor the motor domain, or as a tetramer in combination with two accessory light chains (KLC). To ensure proper cargo distribution, kinesin-1 activity is precisely regulated. Both KLC and KHC subunits bind cargoes or regulatory proteins to engage the motor for movement along micr ...[more]

PMID: 25944905

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Project description:UnlabelledDelivery of proteins and organelles to the growth cone during axon extension relies on anterograde transport by kinesin motors. Though critical for neural circuit development, the mechanisms of cargo-specific anterograde transport during axon extension are only starting to be explored. Cargos of particular importance for axon outgrowth are microtubule modifiers, such as SCG10 (Stathmin-2). SCG10 is expressed solely during axon extension, localized to growth cones, and essential for axon outgrowth; however, the mechanisms of SCG10 transport and activity were still debated. Using zebrafish mutants and in vivo imaging, we identified the Kif1B motor and its interactor Kif1 binding protein (KBP) as critical for SCG10 transport to axon growth cones and complete axon extension. Axon truncation in kbp(st23) mutants can be suppressed by SCG10 overexpression, confirming the direct relationship between decreased SCG10 levels and failed axon outgrowth. Live imaging revealed that the reduced levels of SCG10 in kbp(st23) mutant growth cones led to altered microtubule stability, defining the mechanistic basis of axon truncation. Thus, our data reveal a novel role for the Kif1B-KBP complex in the anterograde transport of SCG10, which is necessary for proper microtubule dynamics and subsequent axon extension.Significance statementTogether, our data define the mechanistic underpinnings of failed axon outgrowth with loss of KBP or its associated motor, Kif1B. In addition, we provide conclusive evidence that this defect results from disruption of anterograde transport of SCG10. This is one of the first examples of a motor to be implicated in the essential transport of a discreet cargo necessary for axon extension. In addition, counter to previous in vitro and cell culture results, neither loss of the Kif1B motor nor KBP resulted in inhibition of mitochondrial transport. Altogether, our work links transport of SCG10 to the regulation of microtubule dynamics in the axon growth cone and enhances our understanding of this process during axon outgrowth.

Dataset Information

JIP3 Activates Kinesin-1 Motility to Promote Axon Elongation.

Publications

JIP3 Activates Kinesin-1 Motility to Promote Axon Elongation.

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