ADAR1-dependent editing regulates human beta cell transcriptome diversity during inflammation

Szymczak, F.; Cohen-Fultheim, R.; Thomaidou, S.; Brachene, A.C. de; Castela, A.; Colli, M.; Marchetti, P.; Levanon, E.; Eizirik, D.; Zaldumbide, A.

doi:doi:10.3389/fendo.2022.1058345

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-beta H1 cells exposed to IFN alpha or IFN gamma/IL1 beta, we evaluated the role of ADAR1 in human pancreatic beta cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing.
Results: We show that both IFN alpha and IFN gamma/IL1 beta stimulation promote ADAR1 expression and increase the A-to-I...Show moreIntroduction: 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-beta H1 cells exposed to IFN alpha or IFN gamma/IL1 beta, we evaluated the role of ADAR1 in human pancreatic beta cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing.
Results: We show that both IFN alpha and IFN gamma/IL1 beta stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-beta H1 cells as well as in primary human islets.
Discussion: We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFN alpha effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the beta cell transcriptome under inflammatory conditions.Show less

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ADAR1-dependent editing regulates human beta cell transcriptome diversity during inflammation