Kinesin‐1/Hsc70‐dependent mechanism of slow axonal transport and its relation to fast axonal transport
Kinesin‐1/Hsc70‐dependent mechanism of slow axonal transport and its relation to fast axonal transport
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DOI：
10.1038/emboj.2009.389
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发表时间：
2010-02
期刊：
影响因子：
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通讯作者：
S. Terada;M. Kinjo;M. Aihara;Y. Takei;N. Hirokawa
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文献类型：
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作者：
S. Terada;M. Kinjo;M. Aihara;Y. Takei;N. Hirokawa
轴突中的细胞质蛋白运输（“慢轴突运输”）对于神经元稳态至关重要，并且涉及驱动蛋白-1，它与膜细胞器运输（“快速轴突运输”）相同。然而，慢速轴突运输的分子机制以及慢速和快速轴突运输之间的驱动蛋白-1 使用差异一直难以捉摸。在这里，我们发现缓慢的轴突运输取决于驱动蛋白-1运动复合物中驱动蛋白轻链的 DnaJ 样结构域与 Hsc70（细胞质蛋白和驱动蛋白-1之间的支架）之间的相互作用。该结构域位于四肽重复序列内，可与膜细胞器结合，鱿鱼巨轴突中该结构域的竞争性扰动破坏了细胞质蛋白运输并增强了膜细胞器运输，表明该结构域可能具有作为 Hsc70 慢速和快速运输之间的转换系统的功能。过度表达该结构域的显性失活形式的转基因小鼠表现出慢速运输延迟、快速运输加速和视轴突病变。这些发现为细胞内转运的调节机制及其在神经元功能障碍中的有趣意义提供了基础。
Cytoplasmic protein transport in axons (‘slow axonal transport’) is essential for neuronal homeostasis, and involves Kinesin‐1, the same motor for membranous organelle transport (‘fast axonal transport’). However, both molecular mechanisms of slow axonal transport and difference in usage of Kinesin‐1 between slow and fast axonal transport have been elusive. Here, we show that slow axonal transport depends on the interaction between the DnaJ‐like domain of the kinesin light chain in the Kinesin‐1 motor complex and Hsc70, scaffolding between cytoplasmic proteins and Kinesin‐1. The domain is within the tetratricopeptide repeat, which can bind to membranous organelles, and competitive perturbation of the domain in squid giant axons disrupted cytoplasmic protein transport and reinforced membranous organelle transport, indicating that this domain might have a function as a switchover system between slow and fast transport by Hsc70. Transgenic mice overexpressing a dominant‐negative form of the domain showed delayed slow transport, accelerated fast transport and optic axonopathy. These findings provide a basis for the regulatory mechanism of intracellular transport and its intriguing implication in neuronal dysfunction.