Kinesin superfamily motor proteins and intracellular transport

Hirokawa, Nobutaka; Noda, Yasuko; Tanaka, Yosuke; Niwa, Shinsuke

doi:10.1038/nrm2774

Cited by 1,524 publications

(1,547 citation statements)

References 155 publications

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“…We analyzed the axonal distribution of mitochondria and amyloid precursor protein (APP), which are kinesin-1 cargoes, and of synaptophysin (SYP) and synaptotagmin 1 (SYT1), which are kinesin-3 cargoes, 4 in uninfected control (Jsap1 f/f :Jlp f/f ) and AxCANCre-infected Jsap1:Jlp dKO hippocampal neurons at 7 d.p.i. All of the cargoes were almost uniformly distributed in the axons of control neurons, whereas the kinesin-1 cargoes appeared to accumulate in the swollen axons of the dKO neurons (Figures 3a and b).…”

Section: Resultsmentioning

confidence: 99%

“…3 Neuronal kinesin-1 often transports its cargoes through adaptor proteins such as c-Jun NH 2 -terminal kinase (JNK)-interacting protein 1 (JIP1) and JNK/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JIP3 or Sunday Driver). 4 The JIP protein family includes JIP1, 5 JIP2, 6 JSAP1/JIP3 (Ito et al 1999; Kelkar et al 2000) and JNK-associated leucine zipper protein (JLP). 9 Splice variants of JLP are known as JIP4 (Kelkar et al 2005) or SPAG9.…”

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JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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Axonal transport is critical for neuronal development and function, and defective axonal transport has been implicated in neurodegenerative diseases. However, how axonal transport is regulated, or how defective transport leads to neuronal degeneration, remains unclear. Here, we report that c-Jun NH 2 -terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) and JNK-associated leucine zipper protein (JLP) are essential for postnatal brain development. Mice with a double-knockout (dKO) in Jsap1 and Jlp in the dorsal telencephalon developed progressive neuron loss. Using a primary neuron culture system with induced disruption of targeted genes, combined with gene rescue experiments, we show that JSAP1 and JLP regulate kinesin-1-dependent axonal transport with functional redundancy. We also show that the binding of JSAP1 and JLP to kinesin-1 heavy chain is crucial for interactions between kinesin-1 and microtubules. Furthermore, we describe a molecular mechanism by which defective kinesin-1-dependent axonal transport in Jsap1:Jlp dKO neurons causes axonal degeneration and subsequent neuronal death. JNK hyperactivation because of increased intra-axonal Ca 2+ in the Jsap1:Jlp dKO neurons was found to mediate both the axonal degeneration and neuronal death, in cooperation with the Ca 2+ -dependent protease calpain. Our results indicate that axonal JNK may relocate to the nucleus in a dynein-dependent manner, where it activates the transcription factor c-Jun, resulting in neuronal death. Taken together, our data establish JSAP1 and JLP as positive regulators of kinesin-1-dependent axonal transport, which prevents neuronal degeneration.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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“…A simplified classification defines 14 major subfamilies of kinesins 14 , albeit recent work indicates that this scheme may need expansion 10 . The KIF classification 15 is finer grained but refers only to mammalian kinesins. Figure 2 shows the topology of those kinesins that are known to have a role in mitosis.…”

Section: Structure and Domain Organization Of Mitotic Kinesinsmentioning

confidence: 99%

Prime movers: the mechanochemistry of mitotic kinesins

Cross

McAinsh

2014

Nat Rev Mol Cell Biol

187

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“…Interaction of these vesicles with microtubules is mediated by motor proteins that provide the force necessary to move them along the tubulin tracks. Vesicle‐associated motors are of two types depending on the direction in which the vesicle is transported: plus‐end‐directed motor proteins ( N‐kinesins ) that transport vesicles toward the cellular periphery and minus‐end‐directed motor proteins (dynein and members of the C‐kinesin family such as KIFC2 and KIFC3) that move vesicles to the perinuclear area (Hirokawa, Noda, Tanaka & Niwa, 2009). …”

Section: Introductionmentioning

confidence: 99%

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

et al. 2018

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SummaryInability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule‐based minus‐end‐directed motor proteins, the well‐characterized dynein, and the less‐studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti‐aging purposes.

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Kinesin superfamily motor proteins and intracellular transport

Cited by 1,524 publications

References 155 publications

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

Prime movers: the mechanochemistry of mitotic kinesins

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

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