The fail-safe mechanism of post-transcriptional silencing of unspliced HAC1 mRNA
The fail-safe mechanism of post-transcriptional silencing of unspliced HAC1 mRNA
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DOI：
10.7554/elife.20069
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发表时间：
2016-10-01
期刊：
影响因子：
7.7
通讯作者：
Weinberg, David E.
中科院分区：
文献类型：
--
作者：
Di Santo, Rachael;Aboulhouda, Soufiane;Weinberg, David E.
HAC 1编码的转录因子是芽殖酵母中未折叠蛋白反应（UPR）的中心效应子。当UPR失活时，Hac 1 mRNA以未剪接的同种型储存在细胞质中，并且检测不到Hac 1蛋白。内含子的去除是必要的和足够的，以减轻转录后沉默的HAC 1 mRNA，但内含子防止Hac 1蛋白积累的确切机制仍然难以捉摸。在这里，我们表明，抑制翻译起始和加速蛋白质降解的组合-这两个依赖于内含子-防止积累的Hac 1蛋白时，不饱和聚酯树脂是无活性的。在功能上，需要这种故障安全沉默机制的两个组件来防止Hac 1蛋白的异位产生和UPR的伴随激活。我们的研究结果提供了一个机制的理解，HAC 1调控，并揭示了一种新的策略，完全转录后沉默的细胞质mRNA。
HAC1 encodes a transcription factor that is the central effector of the unfolded protein response (UPR) in budding yeast. When the UPR is inactive, HAC1 mRNA is stored as an unspliced isoform in the cytoplasm and no Hac1 protein is detectable. Intron removal is both necessary and sufficient to relieve the post-transcriptional silencing of HAC1 mRNA, yet the precise mechanism by which the intron prevents Hac1 protein accumulation has remained elusive. Here, we show that a combination of inhibited translation initiation and accelerated protein degradation - both dependent on the intron - prevents the accumulation of Hac1 protein when the UPR is inactive. Functionally, both components of this fail-safe silencing mechanism are required to prevent ectopic production of Hac1 protein and concomitant activation of the UPR. Our results provide a mechanistic understanding of HAC1 regulation and reveal a novel strategy for complete post-transcriptional silencing of a cytoplasmic mRNA.