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德国马克斯普朗克生物化学研究所F. Ulrich Hartl等研究人员合作发现，通读缓解的机制揭示GCN1介导翻译质量控制的原则。该研究于2023年6月19日在线发表于国际一流学术期刊《细胞》。

研究人员在线虫和哺乳动物细胞中显示，通读蛋白是由涉及BAG6伴侣复合物和核糖体碰撞感应蛋白GCN1的一个耦合的两级质量控制途径所靶向的。具有疏水性C端延伸（CTE）的通读蛋白被SGTA-BAG6识别，并被RNF126泛素化以进行蛋白酶体降解。此外，由GCN1和CCR4/NOT启动的共翻译mRNA降解限制了通读产物的积累。出乎意料的是，选择性核糖体分析发现，当核糖体在非最佳密码子处发生碰撞时，GCN1在调节翻译动态方面具有普遍作用，这些密码子富含3′UTR、跨膜蛋白和胶原蛋白。GCN1功能障碍在衰老过程中越来越多地扰乱这些蛋白质类别，导致mRNA和蛋白质组的不平衡。这些结果将GCN1定义为翻译过程中维持蛋白质平衡的一个关键因素。

据介绍，对mRNA 3′非翻译区（3′UTR）的通读会导致产生异常的蛋白质。后生动物能有效地清除通读蛋白，但其基本机制仍不清楚。

附：英文原文

Title: Mechanisms of readthrough mitigation reveal principles of GCN1-mediated translational quality control

Author: Martin B.D. Müller, Prasad Kasturi, Gopal G. Jayaraj, F. Ulrich Hartl

Issue&Volume: 2023-06-19

Abstract: Readthrough into the 3′ untranslated region (3′ UTR) of the mRNA results in the production of aberrant proteins. Metazoans efficiently clear readthrough proteins, but the underlying mechanisms remain unknown. Here, we show in Caenorhabditis elegans and mammalian cells that readthrough proteins are targeted by a coupled, two-level quality control pathway involving the BAG6 chaperone complex and the ribosome-collision-sensing protein GCN1. Readthrough proteins with hydrophobic C-terminal extensions (CTEs) are recognized by SGTA-BAG6 and ubiquitylated by RNF126 for proteasomal degradation. Additionally, cotranslational mRNA decay initiated by GCN1 and CCR4/NOT limits the accumulation of readthrough products. Unexpectedly, selective ribosome profiling uncovered a general role of GCN1 in regulating translation dynamics when ribosomes collide at nonoptimal codons, enriched in 3′ UTRs, transmembrane proteins, and collagens. GCN1 dysfunction increasingly perturbs these protein classes during aging, resulting in mRNA and proteome imbalance. Our results define GCN1 as a key factor acting during translation in maintaining protein homeostasis.

DOI: 10.1016/j.cell.2023.05.035

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00587-1