ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress

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 trans...

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Detalles Bibliográficos
Autores: Guallar Artal, Diana, Fuentes Iglesias, Alejandro, Souto Becerra, Yara, Ameneiro Quiñoy, Cristina, Freire-Agulleiro, Óscar, Pardavila Paz, José Ángel, Escudero Pérez, Adriana, García Outeiral, Vera, Moreira, Tiago Martins, Sáenz, Carmen, Xiong, Heng, Liu, Dongbing, Xiao, Shidi, Hou, Yong, Wu, Kui, Torrecilla Cillero, Daniel, Hartner, Jochen C., González Blanco, Miguel, Lee, Leo J., López Yoldi, Miguel, Fidalgo Pérez, Miguel Ángel
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad de Santiago de Compostela (USC)
Repositorio:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
Idioma:inglés
OAI Identifier:oai:minerva.usc.gal:10347/38592
Acceso en línea:https://hdl.handle.net/10347/38592
Access Level:acceso abierto
Palabra clave:RNA A-to-I editing
ADAR1
Somatic cell reprogramming
iPSC
Pluripotency
MET
ER stress
UPR
Innate immune response
Subcellular localization
32 Ciencias médicas
Descripción
Sumario: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

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