Modulation of nonsense mediated decay by rapamycin.
Modulation of nonsense mediated decay by rapamycin.
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DOI：
10.1093/nar/gkw1109
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发表时间：
2017-04-07
影响因子：
14.9
通讯作者：
Sanford JR
中科院分区：
文献类型：
--
作者：
Martinez-Nunez RT;Wallace A;Coyne D;Jansson L;Rush M;Ennajdaoui H;Katzman S;Bailey J;Deinhardt K;Sanchez-Elsner T;Sanford JR
雷帕霉素是一种天然存在的大环内酯，其靶标是多种物种中营养和应激调节的核心。尽管作为帽依赖性mRNA翻译的抑制剂的作用已经确立，但关于其对其他RNA加工模式的影响知之甚少。在这里，我们的特点景观雷帕霉素诱导的转录后基因调控。雷帕霉素处理的细胞的转录组分析揭示了选择性mRNA剪接的全基因组变化和NMD敏感亚型的显著变化。我们证明，尽管有充分的证据证明帽依赖的mRNA翻译衰减，雷帕霉素可以增加某些转录的NMD。雷帕霉素治疗显著降低内源性和外源性的提前终止密码子（PTC）的mRNA亚型的水平，其效果是剂量，UPF1和4EBP依赖性。与非PTC同种型相比，含PTC的SRSF6转录物在雷帕霉素治疗后表现出较短的半衰期。雷帕霉素治疗也会导致多聚核糖体中含有PTC的mRNA亚型的耗竭，这强调了翻译和NMD之间的功能关系。增强的NMD活性也与雷帕霉素处理的细胞中核帽结合复合物（CBC）的富集相关。我们的数据表明，雷帕霉素通过NMD调节全球RNA稳态。
Rapamycin is a naturally occurring macrolide whose target is at the core of nutrient and stress regulation in a wide range of species. Despite well-established roles as an inhibitor of cap-dependent mRNA translation, relatively little is known about its effects on other modes of RNA processing. Here, we characterize the landscape of rapamycin-induced post-transcriptional gene regulation. Transcriptome analysis of rapamycin-treated cells reveals genome-wide changes in alternative mRNA splicing and pronounced changes in NMD-sensitive isoforms. We demonstrate that despite well-documented attenuation of cap-dependent mRNA translation, rapamycin can augment NMD of certain transcripts. Rapamycin-treatment significantly reduces the levels of both endogenous and exogenous Premature Termination Codon (PTC)-containing mRNA isoforms and its effects are dose-, UPF1- and 4EBP-dependent. The PTC-containing SRSF6 transcript exhibits a shorter half-life upon rapamycin-treatment as compared to the non-PTC isoform. Rapamycin-treatment also causes depletion of PTC-containing mRNA isoforms from polyribosomes, underscoring the functional relationship between translation and NMD. Enhanced NMD activity also correlates with an enrichment of the nuclear Cap Binding Complex (CBC) in rapamycin-treated cells. Our data demonstrate that rapamycin modulates global RNA homeostasis by NMD.