Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology.
Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology.
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DOI：
10.7554/elife.66904
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发表时间：
2021-04-26
期刊：
影响因子：
7.7
通讯作者：
Ackerman SL
中科院分区：
文献类型：
--
作者：
Terrey M;Adamson SI;Chuang JH;Ackerman SL
翻译依赖的质量控制途径，如不进行衰变（NGD），不停止衰变（NSD）和无义介导的衰变（NMD），通过解析非翻译核糖体和防止产生来自错误和异常mRNA的潜在毒性肽来控制蛋白质合成和蛋白质稳态。然而，翻译是如何改变的，以及在缺乏这些途径的情况下出现的体内缺陷还知之甚少。在这里，我们表明，NGD/NSD因子Pelo和Hbs 1 l是至关重要的小鼠小脑神经发生，但消耗这些神经元的生存后发展。突变小鼠胚胎成纤维细胞的分析揭示了翻译暂停，信号通路的改变，和翻译重编程。在缺失NMD因子Upf 2后，观察到对信号传导途径的类似影响，包括mTOR活化、翻译组和小鼠小脑发育。我们的数据表明，这些质量控制途径，功能，以减轻错误的不同步骤的翻译可以引起类似的细胞反应。
Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD), and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical in mice for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant mouse embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, including mTOR activation, the translatome and mouse cerebellar development were observed upon deletion of the NMD factor Upf2. Our data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses.
影响因子：
2.7
作者：
Guo, Qiuxia;Li, Kairong;Sunmonu, N. Abimbola;Li, James Y. H.
通讯作者：
Li, James Y. H.