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衰老会加剧核糖体暂停以破坏共翻译蛋白质稳定

Kevin C Stein¹, Fabián Morales-Polanco¹, Joris van der Lienden¹

¹Department of Biology, Stanford University, Stanford, CA, USA.

|January 20, 2022

概括

衰老会通过增加核糖体在翻译过程中的暂停来损害细胞蛋白质的质量控制. 这导致错误折叠的蛋白质积累,并导致与年龄相关的衰退.

科学领域:

分子生物学
老年学
细胞生物学

背景情况:

随着年龄的增长,细胞蛋白质稳定性下降,导致蛋白质错折疾病.
老龄化损害蛋白质稳定性的机制尚未完全理解.
新生的多对蛋白质稳定网络构成重大挑战.

研究的目的:

调查老化过程中的转化效率改变导致蛋白质稳定性崩的假设.
阐明核糖体暂停和核糖体相关质量控制 (RQC) 在衰老过程中的作用.

主要方法:

在年龄的Caenorhabditis elegans和Saccharomyces cerevisiae中对翻译延长动力学的比较分析.
识别核糖体暂停点,包括多基延伸点.
在老化的酵母中评估RQC基质清除和聚合.
在酵母突变中,寿命与核糖体暂停和RQC通路流的相关性.

主要成果:

老化改变了翻译延长动力学,加剧了酵母和虫中的特定位点的核糖体暂停.
增加核糖体暂停导致核糖体碰撞并触发RQC通路.
陈旧的酵母细胞显示RQC基质清除受损并增加聚合.
长寿的酵母突变体表现出年龄相关的核糖体暂停和增强的RQC流.
在C. elegans中,新生的多具有年龄依赖的核糖体暂停,并富含年龄依赖的蛋白质聚合物.

结论:

在衰老过程中增加的核糖体暂停会压倒RQC通路,导致新生的多聚合.
这种RQC过载在衰老过程中对蛋白质稳定性损害和全身性衰退有重大影响.
针对翻译效率和RQC可能是缓解与年龄相关的蛋白质稳定性下降的潜在策略.

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