Department of Life Science and Biotechnology, Jadavpur University, Kolkata 700 032, West Bengal, India.
Nucleic Acids Res. 2018 Feb 16;46(3):1139-1156. doi: 10.1093/nar/gkx1160.
Unfolded protein response (UPR) is triggered by the accumulation of unfolded proteins in the endoplasmic reticulum (ER), which is accomplished by a dramatic induction of genes encoding ER chaperones. Activation of these genes involves their rapid transcription by Hac1p, encoded by the HAC1 precursor transcript harboring an intron and a bipartite element (3'-BE) in the 3'-UTR. ER stress facilitates intracellular targeting and recruitment of HAC1 pre-mRNA to Ire1p foci (requiring 3'-BE), leading to its non-spliceosomal splicing mediated by Ire1p/Rlg1p. A critical concentration of the pre-HAC1 harboring a functional 3'-BE element is governed by its 3'→5' decay by the nuclear exosome/DRN. In the absence of stress, pre-HAC1 mRNA undergoes a rapid and kinetic 3'→5' decay leading to a precursor pool, the majority of which lack the BE element. Stress, in contrast, causes a diminished decay, thus resulting in the production of a population with an increased abundance of pre-HAC1 mRNA carrying an intact BE, which facilitates its more efficient recruitment to Ire1p foci. This mechanism plays a crucial role in the timely activation of UPR and its prompt attenuation following the accomplishment of homeostasis. Thus, a kinetic mRNA decay provides a novel paradigm for mRNA targeting and regulation of gene expression.
未折叠蛋白反应 (UPR) 是由内质网 (ER) 中未折叠蛋白的积累触发的，这是通过强烈诱导编码 ER 伴侣的基因来实现的。这些基因的激活涉及它们通过 Hac1p 的快速转录，Hac1p 由 HAC1 前体转录本编码，该转录本在 3'-UTR 中含有一个内含子和一个二分元件 (3'-BE)。ER 应激促进 HAC1 前体 mRNA 向 Ire1p 焦点的细胞内靶向和募集（需要 3'-BE），导致其由 Ire1p/Rlg1p 介导的非剪接体剪接。具有功能性 3'-BE 元件的前 HAC1 的临界浓度受核外切酶/DRN 的 3'→5' 降解控制。在没有应激的情况下，前 HAC1 mRNA 经历快速和动态的 3'→5' 降解，导致前体池的产生，其中大多数缺乏 BE 元件。相比之下，应激会导致降解减少，从而导致产生具有更多完整 BE 的前 HAC1 mRNA 的群体，这有利于其更有效地募集到 Ire1p 焦点。这种机制在 UPR 的及时激活及其在实现动态平衡后的迅速衰减中起着至关重要的作用。因此，动态 mRNA 降解为 mRNA 靶向和基因表达调控提供了一个新的范例。
