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未折叠蛋白反应的终止由 ER 应激诱导的 HAC1 mRNA 核滞留所指导。

Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention.

机构信息

Univ Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Hôpital St. Louis 1, Avenue Claude Vellefaux, 75475, Paris Cedex 10, France.

Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France.

出版信息

Nat Commun. 2022 Oct 25;13(1):6331. doi: 10.1038/s41467-022-34133-8.

DOI:10.1038/s41467-022-34133-8
PMID:36284099
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9596429/
Abstract

Cellular homeostasis is maintained by surveillance mechanisms that intervene at virtually every step of gene expression. In the nucleus, the yeast chromatin remodeler Isw1 holds back maturing mRNA ribonucleoparticles to prevent their untimely export, but whether this activity operates beyond quality control of mRNA biogenesis to regulate gene expression is unknown. Here, we identify the mRNA encoding the central effector of the unfolded protein response (UPR) HAC1, as an Isw1 RNA target. The direct binding of Isw1 to the 3' untranslated region of HAC1 mRNA restricts its nuclear export and is required for accurate UPR abatement. Accordingly, ISW1 inactivation sensitizes cells to endoplasmic reticulum (ER) stress while its overexpression reduces UPR induction. Our results reveal an unsuspected mechanism, in which binding of ER-stress induced Isw1 to HAC1 mRNA limits its nuclear export, providing a feedback loop that fine-tunes UPR attenuation to guarantee homeostatic adaptation to ER stress.

摘要

细胞稳态是通过监控机制来维持的，这些监控机制几乎干预了基因表达的每一个步骤。在细胞核中，酵母染色质重塑因子 Isw1 抑制成熟的 mRNA 核糖核蛋白颗粒的出核，以防止它们过早输出，但这种活性是否超出 mRNA 生物发生的质量控制来调节基因表达尚不清楚。在这里，我们确定了编码未折叠蛋白反应 (UPR) 核心效应物 HAC1 的 mRNA 是 Isw1 的 RNA 靶标。Isw1 直接结合 HAC1 mRNA 的 3'非翻译区限制了其核输出，这是准确衰减 UPR 所必需的。因此，ISW1 的失活使细胞对内质网 (ER) 应激敏感，而过表达则减少 UPR 的诱导。我们的研究结果揭示了一种意想不到的机制，即 ER 应激诱导的 Isw1 与 HAC1 mRNA 的结合限制了其核输出，提供了一个反馈回路，精细调节 UPR 的衰减，以保证细胞对内质网应激的稳态适应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/42043ce8b0f7/41467_2022_34133_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/3a55ab1b6872/41467_2022_34133_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/87cb93f1fadf/41467_2022_34133_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/4aa73f5564b6/41467_2022_34133_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/3f86aa72770d/41467_2022_34133_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/655804a1382f/41467_2022_34133_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/2e7e1351d04b/41467_2022_34133_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/42043ce8b0f7/41467_2022_34133_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/3a55ab1b6872/41467_2022_34133_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/87cb93f1fadf/41467_2022_34133_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/4aa73f5564b6/41467_2022_34133_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/3f86aa72770d/41467_2022_34133_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/655804a1382f/41467_2022_34133_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/2e7e1351d04b/41467_2022_34133_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/768d/9596429/42043ce8b0f7/41467_2022_34133_Fig7_HTML.jpg

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