Department of Cell Biology and Anatomy, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
EMBO J. 2010 Feb 17;29(4):843-54. doi: 10.1038/emboj.2009.389. Epub 2010 Jan 28.
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.
细胞质蛋白在轴突中的运输（“慢轴突运输”）对于神经元的内稳态至关重要，涉及驱动蛋白-1（Kinesin-1），这是一种用于膜性细胞器运输的相同的运动蛋白（“快轴突运输”）。然而，慢轴突运输的分子机制以及 Kinesin-1 在慢轴突和快轴突运输中的使用差异一直难以捉摸。在这里，我们表明慢轴突运输依赖于 Kinesin-1 运动复合物中轻链的 DnaJ 样结构域与 Hsc70 之间的相互作用，Hsc70 是细胞质蛋白与 Kinesin-1 之间的支架。该结构域位于四肽重复序列内，可与膜性细胞器结合，在鱿鱼巨大轴突中竞争性地干扰该结构域会破坏细胞质蛋白的运输并增强膜性细胞器的运输，表明该结构域可能通过 Hsc70 作为慢运输和快运输之间的转换系统发挥作用。过表达该结构域的显性失活形式的转基因小鼠显示出慢运输延迟、快运输加速和视神经病变。这些发现为细胞内运输的调节机制及其在神经元功能障碍中的有趣影响提供了基础。
