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

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-transcripti...

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Published in:Journal of autoimmunity 2021-12, Vol.125, p.102755-102755, Article 102755
Main Authors: Vlachogiannis, Nikolaos I., Tual-Chalot, Simon, Zormpas, Eleftherios, Bonini, Francesca, Ntouros, Panagiotis A., Pappa, Maria, Bournia, Vasiliki-Kalliopi, Tektonidou, Maria G., Souliotis, Vassilis L., Mavragani, Clio P., Stamatelopoulos, Kimon, Gatsiou, Aikaterini, Sfikakis, Petros P., Stellos, Konstantinos
Format: Article
Language:English
Subjects:
A-to-I RNA editing
Adenosine - genetics
Adenosine Deaminase - genetics
Adenosine Deaminase - metabolism
Animals
Autoimmunity
Endothelial Cells - metabolism
Gene expression
Humans
Inosine - genetics
Interferon Type I - metabolism
Leukocytes, Mononuclear - metabolism
RNA
RNA Editing
RNA-Binding Proteins - genetics
Scleroderma, Systemic - genetics
Scleroderma, Systemic - metabolism
Systemic sclerosis
Type I interferon
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Summary: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. 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. 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 
ISSN:0896-8411
1095-9157
DOI:10.1016/j.jaut.2021.102755