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衰老加剧核糖体暂停并破坏共翻译的蛋白质稳态
2022-01-23 17:03
来源：小柯机器人

2022年1月19日，《自然》杂志在线发表了美国斯坦福大学Judith Frydman研究团队的最新成果，该研究表明，衰老加剧核糖体暂停并破坏共翻译的蛋白质稳态。

由于新生多肽对蛋白稳态网络来说是一个巨大的负担，研究人员假设衰老过程中翻译效率的改变可能有助于推动蛋白稳态的崩溃。研究人员发现，衰老改变了秀丽隐杆线虫和酿酒酵母的翻译延伸动力学。在衰老的酵母和线虫中，核糖体停顿在特定的位置上加剧，包括polybasic stretches，进而导致核糖体碰撞增加，这已知会触发核糖体相关的质量控制（RQC）。值得注意的是，衰老的酵母细胞表现出清除障碍和RQC底物的聚集增加，这表明衰老压倒了这个途径。事实上，长寿的酵母突变体减少了依赖年龄的核糖体停顿，延长寿命与通过RQC途径的更大通量相关。
 
研究人员进一步将翻译的改变与蛋白稳态的崩溃联系起来，并发现在线虫中表现出年龄依赖性核糖体停顿的新生多肽在年龄依赖性蛋白聚集体中强烈富集。值得注意的是，衰老增加了蛋白状态许多成分的暂停和聚集，这可能会启动一个蛋白状态崩溃的循环。研究人员提出，核糖体暂停的增加能够导致RQC过载和新生多肽的聚集，关键是在衰老过程中促成了蛋白稳态的损害和系统的衰退。
 
据悉，衰老伴随着细胞蛋白稳态的下降，这是许多与年龄有关的蛋白质错误折叠疾病的基础。然而，衰老如何损害蛋白稳态仍不清楚。
 
附：英文原文
 
Title: Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis

Author: Stein, Kevin C., Morales-Polanco, Fabin, van der Lienden, Joris, Rainbolt, T. Kelly, Frydman, Judith

Issue&Volume: 2022-01-19

Abstract: Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases1,2. Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network3, we hypothesized that altered translational efficiency during ageing could help to drive the collapse of proteostasis. Here we show that ageing alters the kinetics of translation elongation in both Caenorhabditis elegans and Saccharomyces cerevisiae. Ribosome pausing was exacerbated at specific positions in aged yeast and worms, including polybasic stretches, leading to increased ribosome collisions known to trigger ribosome-associated quality control (RQC)4,5,6. Notably, aged yeast cells exhibited impaired clearance and increased aggregation of RQC substrates, indicating that ageing overwhelms this pathway. Indeed, long-lived yeast mutants reduced age-dependent ribosome pausing, and extended lifespan correlated with greater flux through the RQC pathway. Further linking altered translation to proteostasis collapse, we found that nascent polypeptides exhibiting age-dependent ribosome pausing in C. elegans were strongly enriched among age-dependent protein aggregates. Notably, ageing increased the pausing and aggregation of many components of proteostasis, which could initiate a cycle of proteostasis collapse. We propose that increased ribosome pausing, leading to RQC overload and nascent polypeptide aggregation, critically contributes to proteostasis impairment and systemic decline during ageing.

DOI: 10.1038/s41586-021-04295-4

Source: https://www.nature.com/articles/s41586-021-04295-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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