E3结合酶AREL1控制了溶酶体的周核定位,并支持普金氏细胞的存活

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Luyi Jiang¹, Jiangfen Tang¹, Ya-Fen Zhang¹

¹State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, 430072, Wuhan, China.

The EMBO journal

|December 2, 2025

概括

与内细胞网关联的AREL1蛋白通过与V-ATPase相互作用来调节 lysosome的定位和功能. 这种AREL1-UBAC2-V-ATPase通路对神经元健康至关重要,因为其破坏会导致运动缺陷和溶酶体功能障碍.

科学领域:

细胞生物学细胞生物学
神经科学是一个神经科学.
分子生物学分子生物学

背景情况:

溶酶体局部化会影响它们的特性,周核溶酶体比周边溶酶体更酸性,更不灵活.
细胞内膜网膜 (ER) 积极调节 lysosome 动力学和通过膜接触部位的功能.

研究的目的:

为了研究ER-居住的抗亡E3无素蛋白联酶1 (AREL1) 在调节 lysosome定位和功能的作用.
阐明了ER介导的核周溶酶体聚类背后的分子机制.

主要方法:

通过基于细胞的测试,研究了AREL1与V-ATPase的相互作用及其在 lysosome定位中的作用.
利用敲除和敲除模型 (包括小鼠) 来评估AREL1和UBAC2对 lysosome 功能和神经元健康的生理影响.
分析了溶酶体的pH值,降解能力和脂素的积累.

主要成果:

通过V-ATPase,AREL1直接与溶解体接触,并调解V1B2亚单元的K33结合的多基化,促进其在周核ER中与UBAC2结合.
由于AREL1或UBAC2的耗尽,导致外周溶酶体分布,溶酶体pH增加和降低降解能力.
敲除ZRANB1 (一个二二基酶) 增强了周核溶酶体聚类,酸度和降解.
阿雷尔1淘汰赛小鼠显示了依赖于年龄的普尔金日细胞损失,动力障碍,运动障碍和溶酶体功能障碍,由利波素积累表明.

结论:

AREL1-UBAC2-V-ATPase轴是溶酶体定位和功能的一个关键调节器.
经ER介导的核周溶酶体局部化在生理上具有重要意义,特别是对于神经元的健康和功能.
这种途径的失调有助于神经退行性表型和 lysosomal 功能障碍.

关键词:

在AREL1中.Lysosomal 定位定位是什么普尔金耶神经元普尔金耶神经元在 UBAC2 中,UBAC2 是 UBAC2 的代码.这是一个V-ATPase.

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