期刊
FRONTIERS IN ENDOCRINOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2022.1058345
关键词
beta cell (beta cell); inflammation; T1D (type 1 diabetes); transcriptome; RNA editing
资金
- Israel Science Foundation [2039/20, 231/21]
- DON Foundation
- Dutch Diabetes Research Foundation
- JDRF
- IMI2-JU [115797, 945268]
- European Union
- European Federation of Pharmaceutical Industries and Associations (EFPIA)
- Leona M. and Harry B. Helmsley Charitable Trust
- Welbio-FNRS (Fonds National de la Recherche Scientifique), Belgium [WELBIO-CR-2019C-04]
- National Institutes of Health Human Islet Research Network Consortium on Beta Cell Death and Survival from Pancreatic B-Cell Gene Networks to Therapy [HIRN-CBDS]) [U01 DK127786]
- Fonds National de la Recherche Scientifique (FNRS, Belgium)
This article investigates the potential impact of viral infection on type 1 diabetes and finds that ADAR1 editing plays a crucial role in regulating the immune response in pancreatic beta cells.
IntroductionEnterovirus 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.MethodsUsing 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.ResultsWe 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.DiscussionWe 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.
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