ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress.
ADAR1
ER stress
MET
RNA A-to-I editing
UPR
iPSC
innate immune response
pluripotency
somatic cell reprogramming
subcellular localization
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
22
08
2019
revised:
02
04
2020
accepted:
23
04
2020
pubmed:
13
5
2020
medline:
28
4
2021
entrez:
13
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32396862
pii: S1934-5909(20)30155-7
doi: 10.1016/j.stem.2020.04.016
pmc: PMC7415614
mid: NIHMS1588666
pii:
doi:
Substances chimiques
RNA, Double-Stranded
0
Inosine
5A614L51CT
Adenosine Deaminase
EC 3.5.4.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
300-314.e11Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM129157
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD095938
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD097268
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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