ADAR1-dependent editing regulates human β cell transcriptome diversity during inflammation
Florian Szymczak, Roni Cohen‐Fultheim, Sofia Thomaidou, Alexandra Coomans de Brachène, Ângela Castela, Máikel L. Colli, Piero Marchetti, Erez Y. Levanon, Décio L. Eizirik, Arnaud Zaldumbide
Abstract
Introduction: Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation. Methods: Using high-throughput RNA sequencing data from human islets and EndoC-βH1 cells exposed to IFNα or IFNγ/IL1β, we evaluated the role of ADAR1 in human pancreatic β cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing. Results: We show that both IFNα and IFNγ/IL1β stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-βH1 cells as well as in primary human islets. Discussion: We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFNα effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the β cell transcriptome under inflammatory conditions.