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Adenosine-to-inosine RNA editing contributes to type I interferon responses in systemic sclerosis

Lookup NU author(s): Dr Nikolaos Vlachogiannis, Dr Simon Tual-ChalotORCiD, Lefteris Zormpas, Professor Kimon Stamatelopoulos, Dr Aikaterini GatsiouORCiD, Professor Konstantinos StellosORCiD

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Abstract

© 2021 The Authors. Objective: Adenosine deaminase acting on RNA-1 (ADAR1) enzyme is a type I interferon (IFN)-stimulated gene (ISG) catalyzing the deamination of adenosine-to-inosine, a process called A-to-I RNA editing. A-to-I RNA editing takes place mainly in Alu elements comprising a primate-specific level of post-transcriptional gene regulation. Whether RNA editing is involved in type I IFN responses in systemic sclerosis (SSc) patients remains unknown. Methods: ISG expression was quantified in skin biopsies and peripheral blood mononuclear cells derived from SSc patients and healthy subjects. A-to-I RNA editing was examined in the ADAR1-target cathepsin S (CTSS) by an RNA editing assay. The effect of ADAR1 on interferon-α/β-induced CTSS expression was assessed in human endothelial cells in vitro. Results: Increased expression levels of the RNA editor ADAR1, and specifically the long ADAR1p150 isoform, and its target CTSS are strongly associated with type I IFN signature in skin biopsies and peripheral blood derived from SSc patients. Notably, IFN-α/β-treated human endothelial cells show 8-10-fold increased ADAR1p150 and 23-35-fold increased CTSS expression, while silencing of ADAR1 reduces CTSS expression by 60-70%. In SSc patients, increased RNA editing rate of individual adenosines located in CTSS 3′ UTR Alu elements is associated with higher CTSS expression (r = 0.36–0.6, P < 0.05 for all). Similar findings were obtained in subjects with activated type I IFN responses including SLE patients or healthy subjects after influenza vaccination. Conclusion: ADAR1p150-mediated A-to-I RNA editing is critically involved in type I IFN responses highlighting the importance of post-transcriptional regulation of proinflammatory gene expression in systemic autoimmunity, including SSc.

Publication metadata

Author(s): Vlachogiannis NI, Tual-Chalot S, Zormpas E, Bonini F, Ntouros PA, Pappa M, Bournia V-K, Tektonidou MG, Souliotis VL, Mavragani CP, Stamatelopoulos K, Gatsiou A, Sfikakis PP, Stellos K

Publication type: Article

Publication status: Published

Journal: Journal of Autoimmunity

Year: 2021

Volume: 125

Print publication date: 01/12/2021

Online publication date: 29/11/2021

Acceptance date: 16/11/2021

Date deposited: 16/12/2021

ISSN (print): 0896-8411

ISSN (electronic): 1095-9157

Publisher: Academic Press

URL: https://doi.org/10.1016/j.jaut.2021.102755

DOI: 10.1016/j.jaut.2021.102755

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