The Barshop Institute for Longevity and Aging Studies, Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
The Barshop Institute for Longevity and Aging Studies, Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
J Cell Sci. 2017 Oct 1;130(19):3388-3398. doi: 10.1242/jcs.207027. Epub 2017 Aug 14.
Because of their functional polarity and elongated morphologies, microtubule-based transport of proteins and organelles is critical for normal neuronal function. The proteasome is required throughout the neuron for the highly regulated degradation of a broad set of protein targets whose functions underlie key physiological responses, including synaptic plasticity and axonal degeneration. Molecularly, the relationship between proteasome transport and the transport of the targets of proteasomes is unclear. The dynein motor complex is required for the microtubule-based motility of numerous proteins and organelles in neurons. Here, we demonstrate that microtubule-based transport of proteasomes within the neuron in utilizes a different dynein light chain to that used by synaptic proteins. Live imaging of proteasomes and synaptic vesicle proteins in axons and synapses finds that these cargoes traffic independently, and that proteasomes exhibit significantly reduced retrograde transport velocities compared to those of synaptic vesicle proteins. Genetic and biochemical analyses reveals that the homolog of the LC8 dynein light chains (mammalian DYNLL1 and DYNLL2), called Cut up, binds proteasomes and functions specifically during their transport. These data support the model that Cut up functions to specify the dynein-mediated transport of neuronal proteasomes.
由于其功能极性和伸长的形态，基于微管的蛋白质和细胞器运输对正常神经元功能至关重要。蛋白酶体在神经元中广泛降解一组广泛的蛋白质靶标，这些靶标的功能是关键的生理反应的基础，包括突触可塑性和轴突变性，都需要蛋白酶体。从分子水平上看，蛋白酶体运输与蛋白酶体靶标的运输之间的关系尚不清楚。动力蛋白复合物是神经元中许多蛋白质和细胞器基于微管的运动所必需的。在这里，我们证明了神经元内蛋白酶体的基于微管的运输利用了与突触蛋白不同的动力蛋白轻链。轴突和突触中蛋白酶体和突触囊泡蛋白的实时成像发现，这些货物是独立运输的，与突触囊泡蛋白相比，蛋白酶体的逆行运输速度显著降低。遗传和生化分析表明，LC8 动力蛋白轻链的同源物（哺乳动物 DYNLL1 和 DYNLL2），称为 Cut up，与蛋白酶体结合，并在其运输过程中特异性发挥作用。这些数据支持 Cut up 功能特异地将神经元蛋白酶体的动力蛋白介导的运输指定的模型。
