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NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation
Genes & Development ( IF 10.5 ) Pub Date : 2022-03-01 , DOI: 10.1101/gad.347690.120
Michelle Huth 1 , Laura Santini 1, 2 , Elena Galimberti 1 , Julia Ramesmayer 1 , Fabian Titz-Teixeira 3 , Robert Sehlke 3 , Michael Oberhuemer 1 , Sarah Stummer 1 , Veronika Herzog 4 , Marius Garmhausen 3 , Merrit Romeike 1, 2 , Anastasia Chugunova 5 , Friederike Leesch 2, 5 , Laurenz Holcik 1, 2, 6 , Klara Weipoltshammer 7 , Andreas Lackner 1 , Christian Schoefer 7 , Arndt von Haeseler 1, 6, 8 , Christa Buecker 1 , Andrea Pauli 5 , Stefan L Ameres 1, 4 , Austin Smith 9 , Andreas Beyer 3, 10, 11 , Martin Leeb 1
Affiliation  

Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2PTC). NMD deficiency leads to translation of the truncated eIF4A2PTC protein. eIF4A2PTC elicits increased mTORC1 activity and translation rates and causes differentiation delays. This establishes a previously unknown feedback loop between NMD and translation initiation. Furthermore, our results show a clear hierarchy in the severity of target deregulation and differentiation phenotypes between NMD effector KOs (Smg5 KO > Smg6 KO > Smg7 KO), which highlights heterodimer-independent functions for SMG5 and SMG7. Together, our findings expose an intricate link between mRNA homeostasis and mTORC1 activity that must be maintained for normal dynamics of cell state transitions.

中文翻译:

NMD 需要通过微调基因表达和调节翻译来实现及时的细胞命运转变

细胞命运转变依赖于转录和翻译程序的平衡重新布线,以介导有序的发育进程。无义介导的 mRNA 衰变 (NMD) 途径的成分与调节胚胎干细胞 (ESC) 分化有关,但确切的机制尚不清楚。在这里,我们显示 NMD 控制翻译起始因子Eif4a2及其提前终止密码子编码同种型 ( Eif4a2 PTC ) 的表达水平。NMD 缺陷导致截短的 eIF4A2 PTC蛋白的翻译。eIF4A2 PTC引起增加的 mTORC1 活性和翻译率并导致分化延迟。这在 NMD 和翻译启动之间建立了一个以前未知的反馈循环。此外,我们的结果显示 NMD 效应 KO(Smg5 KO > Smg6 KO > Smg7 KO)之间靶标失调和分化表型的严重程度具有明显的层次结构,这突出了 SMG5 和 SMG7 的异二聚体独立功能。总之,我们的研究结果揭示了 mRNA 稳态和 mTORC1 活性之间的复杂联系,必须保持这种联系以维持细胞状态转换的正常动态。
更新日期:2022-03-01
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