Suzuki Ryusuke, Gunarta I Ketut, Boldbaatar Jambaldorj, Erdenebaatar Purev, Odongoo Ravdandorj, Yoshioka Katsuji
Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Drug Discov Ther. 2020 Mar 8;14(1):35-41. doi: 10.5582/ddt.2020.01001. Epub 2020 Feb 5.
Lysosomes are involved in many cellular functions, and in turn lysosomal dysfunction underlies a variety of diseases, including cancer and neurodegenerative diseases. Lysosomes are distributed broadly in the cytoplasm and can move throughout the cell in kinesin- and dynein-dependent manners. Although many mechanisms of lysosomal transport have been reported, how lysosomal transport is regulated has yet to be fully elucidated. In this study we analyzed c-Jun NH-terminal kinase-associated leucine zipper protein (JLP), an adaptor of kinesin and dynein motor proteins, and found that lysosomes were localized toward the cell periphery in JLP knockdown cells, leading to the impairment of autophagosome-lysosome fusion. Furthermore, we performed rescue experiments using wild-type JLP and its various deletion mutants. The results indicated that JLP may regulate lysosome localization and autophagy through interaction of JLP with kinesin-1 heavy chain, but not with dynactin p150 or lysosomal transmembrane protein 55b. Our findings provide new insights into the mechanisms of lysosomal trafficking regulation. This study contributes to the understanding of how lysosomes exert their multiple functions, potentially leading to the identification of molecular targets for diseases caused by lysosomal dysfunction.
溶酶体参与许多细胞功能，反过来，溶酶体功能障碍是包括癌症和神经退行性疾病在内的多种疾病的基础。溶酶体广泛分布于细胞质中，并能以依赖驱动蛋白和动力蛋白的方式在整个细胞内移动。尽管已经报道了许多溶酶体运输的机制，但溶酶体运输是如何被调节的尚未完全阐明。在本研究中，我们分析了c-Jun氨基末端激酶相关亮氨酸拉链蛋白（JLP），一种驱动蛋白和动力蛋白运动蛋白的衔接蛋白，发现溶酶体在JLP敲低细胞中定位于细胞周边，导致自噬体-溶酶体融合受损。此外，我们使用野生型JLP及其各种缺失突变体进行了拯救实验。结果表明，JLP可能通过JLP与驱动蛋白-1重链的相互作用来调节溶酶体定位和自噬，而不是与动力蛋白激活蛋白p150或溶酶体跨膜蛋白55b相互作用。我们的发现为溶酶体运输调节机制提供了新的见解。这项研究有助于理解溶酶体如何发挥其多种功能，可能导致识别由溶酶体功能障碍引起的疾病的分子靶点。
