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.

腺苷 RNA 编辑为肌苷（A 到 I）由 ADAR1 催化并显着改变细胞转录组，尽管其在体细胞重编程中的功能作用在很大程度上尚未得到探索。在这里，我们表明，在诱导多能干细胞 (iPSC) 重编程期间，ADAR1 介导的 A-to-I 编辑的缺失会破坏间充质到上皮的转化 (MET)，并阻碍诱导多能性的获得。使用化学和遗传方法，我们表明缺乏依赖 ADAR1 的 RNA 编辑会通过双链 RNA (dsRNA) 传感器 MDA5 诱导异常的先天免疫反应，释放内质网 (ER) 压力并阻碍上皮命运的获得。我们发现 A-to-I 编辑阻碍了 MDA5 传感和隔离编码膜蛋白的 dsRNA，通过激活 PERK 依赖性未折叠蛋白反应途径促进 ER 稳态，从而促进 MET。因此，这项研究确立了 ADAR1 及其 A-to-I 编辑活动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。