ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress
ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress
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DOI：
10.1016/j.stem.2020.04.016
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发表时间：
2020-08-06
期刊：
影响因子：
23.9
通讯作者：
Fidalgo, Miguel
中科院分区：
文献类型：
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作者：
Guallar, Diana;Fuentes-Iglesias, Alejandro;Fidalgo, Miguel
腺苷到肌苷（A到I）的RNA编辑由ADAR 1催化并显著改变细胞转录组，尽管其在体细胞重编程中的功能作用在很大程度上尚未探索。在这里，我们发现ADAR 1介导的A-to-I编辑的丢失在诱导多能干细胞（iPSC）重编程期间破坏了间充质到上皮的转变（MET），并阻碍了诱导多能性的获得。使用化学和遗传学方法，我们表明，ADAR 1依赖性RNA编辑的缺乏通过双链RNA（dsRNA）传感器MDA 5诱导异常的先天免疫反应，释放内质网（ER）应激并阻碍上皮细胞命运的获得。我们发现，A-to-I编辑阻碍了MDA 5传感和编码膜蛋白的dsRNA的隔离，这通过激活PERK依赖性未折叠蛋白反应途径来促进ER稳态，从而促进MET。因此，这项研究确立了ADAR 1及其A-to-I编辑活性在细胞命运转变过程中的关键作用，并描绘了MET控制有效重编程的关键调控层。
RNA editing of adenosine to inosine (A to I) is catalyzed by ADAR1 and dramatically alters the cellular transcriptome, although its functional roles in somatic cell reprogramming are largely unexplored. Here, we show that loss of ADAR1-mediated A-to-I editing disrupts mesenchymal-to-epithelial transition (MET) during induced pluripotent stem cell (iPSC) reprogramming and impedes acquisition of induced pluripotency. Using chemical and genetic approaches, we show that absence of ADAR1-dependent RNA editing induces aberrant innate immune responses through the double-stranded RNA (dsRNA) sensor MDA5, unleashing endoplasmic reticulum (ER) stress and hindering epithelial fate acquisition. We found that A-to-I editing impedes MDA5 sensing and sequestration of dsRNAs encoding membrane proteins, which promote ER homeostasis by activating the PERK-dependent unfolded protein response pathway to consequently facilitate MET. This study therefore establishes a critical role for ADAR1 and its A-to-I editing activity during cell fate transitions and delineates a key regulatory layer underlying MET to control efficient reprogramming.