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

Frontiers in Endocrinology, vol. 13, pp. 1058345

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.

Authors 10

1. Florian Szymczak

   Université Libre de Bruxelles

   Affiliation as printed

   ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

2. Roni Cohen‐Fultheim

   Bar-Ilan University

   Affiliation as printed

   Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, Israel

3. Sofia Thomaidou Aachen Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands

4. Alexandra Coomans de Brachène

   Université Libre de Bruxelles

   Affiliation as printed

   ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

5. Ângela Castela

   Université Libre de Bruxelles

   Affiliation as printed

   ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

6. Máikel L. Colli

   Université Libre de Bruxelles

   Affiliation as printed

   ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

7. Piero Marchetti

   University of Pisa

   Affiliation as printed

   Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

8. Erez Y. Levanon

   Bar-Ilan University

   Affiliation as printed

   Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, Israel

9. Decio Laks Eizirik

   Université Libre de Bruxelles

   Affiliation as printed

   ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

10. Arnaud Zaldumbide corresponding Aachen Department of Cell and Chemical Biology

    Leiden University Medical Center

    Affiliation as printed

    Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands