University of Bern, Department of Chemistry, Biochemistry and Pharmaceutical Sciences, Bern, Switzerland.
RNA Biol. 2022;19(1):609-621. doi: 10.1080/15476286.2022.2065116. Epub 2021 Dec 31.
Cells of metazoans respond to internal and external stressors by activating stress response pathways that aim for re-establishing cellular homoeostasis or, if this cannot be achieved, triggering programmed cell death. Problems during translation, arising from defective mRNAs, tRNAs, ribosomes or protein misfolding, can activate stress response pathways as well as mRNA surveillance and ribosome quality control programs. Recently, ribosome collisions have emerged as a central signal for translational stress and shown to elicit different stress responses. Here, we review our current knowledge about the intricate mutual connections between ribosome collisions, stress response pathways and mRNA surveillance. A central factor connecting the sensing of collided ribosomes with degradation of the nascent polypeptides, dissociation of the stalled ribosomes and degradation of the mRNA by no-go or non-stop decay is the E3-ligase ZNF598. We tested whether ZNF598 also plays a role in nonsense-mediated mRNA decay (NMD) but found that it is dispensable for this translation termination-associated mRNA surveillance pathway, which in combination with other recent data argues against stable ribosome stalling at termination codons being the NMD-triggering signal.
真核生物的细胞通过激活应激反应途径来应对内部和外部应激源，这些途径旨在重新建立细胞内的稳态，或者如果无法实现，则触发程序性细胞死亡。翻译过程中出现的问题，如 mRNA、tRNA、核糖体或蛋白质折叠缺陷，也可以激活应激反应途径以及 mRNA 监测和核糖体质量控制程序。最近，核糖体碰撞已成为翻译应激的一个核心信号，并显示出不同的应激反应。在这里，我们回顾了我们目前对核糖体碰撞、应激反应途径和 mRNA 监测之间错综复杂的相互联系的了解。连接碰撞核糖体的感应与新生多肽的降解、stalled ribosomes 的解离以及无义或非停衰变降解 mRNA 的核心因素是 E3 连接酶 ZNF598。我们测试了 ZNF598 是否也在无义介导的 mRNA 降解 (NMD) 中发挥作用，但发现它对于这种与翻译终止相关的 mRNA 监测途径是可有可无的，这与其他最近的数据一起表明，终止密码子处的核糖体稳定stalling 不是 NMD 触发信号。
