Ishibashi Kota, Shichino Yuichi, Han Peixun, Wakabayashi Kimi, Mito Mari, Inada Toshifumi, Kimura Seisuke, Iwasaki Shintaro, Mishima Yuichiro
Department of Frontier Life Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan.
RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama, Japan.
PLoS Biol. 2024 Dec 5;22(12):e3002887. doi: 10.1371/journal.pbio.3002887. eCollection 2024 Dec.
Quality control of translation is crucial for maintaining cellular and organismal homeostasis. Obstacles in translation elongation induce ribosome collision, which is monitored by multiple sensor mechanisms in eukaryotes. The E3 ubiquitin ligase Znf598 recognizes collided ribosomes, triggering ribosome-associated quality control (RQC) to rescue stalled ribosomes and no-go decay (NGD) to degrade stall-prone mRNAs. However, the impact of RQC and NGD on maintaining the translational homeostasis of endogenous mRNAs has remained unclear. In this study, we investigated the endogenous substrate mRNAs of NGD during the maternal-to-zygotic transition (MZT) of zebrafish development. RNA-Seq analysis of zebrafish znf598 mutant embryos revealed that Znf598 down-regulates mRNAs encoding the C2H2-type zinc finger domain (C2H2-ZF) during the MZT. Reporter assays and disome profiling indicated that ribosomes stall and collide while translating tandem C2H2-ZFs, leading to mRNA degradation by Znf598. Our results suggest that NGD maintains the quality of the translatome by mitigating the risk of ribosome collision at the abundantly present C2H2-ZF sequences in the vertebrate genome.
翻译的质量控制对于维持细胞和机体的稳态至关重要。翻译延伸过程中的障碍会引发核糖体碰撞，真核生物中有多种传感机制对其进行监测。E3泛素连接酶Znf598识别碰撞的核糖体，触发核糖体相关质量控制（RQC）以拯救停滞的核糖体，并引发无义介导的mRNA降解（NGD）以降解易停滞的mRNA。然而，RQC和NGD对维持内源性mRNA翻译稳态的影响仍不清楚。在本研究中，我们调查了斑马鱼发育的母源-合子转变（MZT）过程中NGD的内源性底物mRNA。对斑马鱼znf598突变体胚胎的RNA测序分析表明，在MZT期间，Znf598下调编码C2H2型锌指结构域（C2H2-ZF）的mRNA。报告基因检测和二聚体分析表明，核糖体在翻译串联C2H2-ZF时会停滞并碰撞，导致Znf598介导的mRNA降解。我们的结果表明，NGD通过降低脊椎动物基因组中大量存在的C2H2-ZF序列处核糖体碰撞的风险来维持翻译组的质量。
