Cell Stem Cell
Volume 27, Issue 2, 6 August 2020, Pages 300-314.e11
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Article
ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress

https://doi.org/10.1016/j.stem.2020.04.016Get rights and content
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Highlights

  • A-to-I RNA editing by ADAR1 is essential for epithelial cell fate acquisition

  • ADAR1 loss induces ER stress that abrogates MET and hinders iPSC reprogramming

  • MDA5 is required to trigger IIR and ER stress responses in the absence of A-to-I editing

  • RNA editing regulates dsRNA compartmentalization and proper UPR function

Summary

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.

Keywords

RNA A-to-I editing
ADAR1
somatic cell reprogramming
iPSC
pluripotency
MET
ER stress
UPR
innate immune response
subcellular localization

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15

These authors contributed equally

16

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