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TRIM9和TRIM26与UBQLN2^P497H相互作用,以调节其蛋白质体降解

Xingyuan Chen¹, Zhongwen Cao¹, Xiaochen Liang¹

¹Environmental Toxicology Graduate Program, University of California, Riverside, California 92521, United States.

ACS chemical biology

|January 26, 2026

概括

肌缩侧面硬化症 (ALS) 研究显示,UBQLN2突变会破坏蛋白质稳定. 新的发现确定TRIM9和TRIM26是UBQLN2^P497H的关键相互作用体,影响蛋白质降解,并可能导致ALS.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

肌缩侧面硬化症 (ALS) 是一种致命的神经退行性疾病,以运动神经元损失为标志.
UBQLN2中的突变与ALS有关,导致蛋白质聚合并破坏蛋白质平衡 (细胞蛋白质平衡).
这些与ALS相关的UBQLN2突变的特定蛋白质相互作用和功能后果尚不清楚.

研究的目的:

描述野生型UBQLN2和两个ALS相关变体 (UBQLN2^P497H和UBQLN2^P497S) 的互动体.
确定突变特异性蛋白质相互作用,并研究它们在ALS病变发生中的功能相关性.

主要方法:

采用APEX2近距离标记来绘制蛋白质相互作用的地图.
使用生物化的亲和度丰富和LC-MS/MS分析.
通过共免疫沉和西部斑分析验证了关键相互作用.

主要成果:

鉴定了785种独特的生物化蛋白质,其中许多蛋白质在UBQLN2突变体周围的丰富度增加,与野生类型相比.
在UBQLN2^P497H附近发现了E3泛素连接酶TRIM9和TRIM26的选择性丰富.
证明UBQLN2^P497H是TRIM9/TRIM26介导的泛基化和蛋白质体降解的基质,涉及一个特定的C端片段.

结论:

TRIM9和TRIM26被确定为UBQLN2^P497H的特定相互作用体.
这些E3结合酶调节了以前未经表征的C端UBQLN2片段的降解.
这种UBQLN2片段的清除受损可能在ALS的发病过程中发挥作用.

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