Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA–triggered innate immune responses

Abstract

Herbert “Herb” Tabor, who celebrated his 100th birthday this past year, served the Journal of Biological Chemistry as a member of the Editorial Board beginning in 1961, as an Associate Editor, and as Editor-in-Chief for 40 years, from 1971 until 2010. Among the many discoveries in biological chemistry during this period was the identification of RNA modification by C6 deamination of adenosine (A) to produce inosine (I) in double-stranded (ds) RNA. This posttranscriptional RNA modification by adenosine deamination, known as A-to-I RNA editing, diversifies the transcriptome and modulates the innate immune interferon response. A-to-I editing is catalyzed by a family of enzymes, adenosine deaminases acting on dsRNA (ADARs). The roles of A-to-I editing are varied and include effects on mRNA translation, pre-mRNA splicing, and micro-RNA silencing. Suppression of dsRNA-triggered induction and action of interferon, the cornerstone of innate immunity, has emerged as a key function of ADAR1 editing of self (cellular) and nonself (viral) dsRNAs. A-to-I modification of RNA is essential for the normal regulation of cellular processes. Dysregulation of A-to-I editing by ADAR1 can have profound consequences, ranging from effects on cell growth and development to autoimmune disorders.

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

“…Although the association with Type-I and Type-II interferons suggested immune activation in vivo, the ISGs IRF1 and IRF2 29 were not coinduced, indicative of suppressed downstream signaling and/or pathway inhibition. 33,39,40 Taken together, these data suggest that the presumably protective effects of RIG-I activation and interferon production become neutralized, and finally overridden, by checkpointdependent immunosuppression as well as infiltration with Tregs and direct pathway inhibition through EZH2. This observation suggests that in OC, RIG-I expression (but not necessarily activity) is uncoupled from negative EZH2-control.…”

“…4c and data not shown). 33 To broaden the concept of immune suppression and establish a potential basis for the association of RIG-I with unfavorable OC outcome, we determined the expression levels of checkpoint molecules 34 as well as a fate-specifying transcription factor of regulatory T cells (Tregs). 4d).…”

“…This suggested that the innate immune response in ovarian tumors may be antagonized by ADAR1. 33 To broaden the concept of immune suppression and establish a potential basis for the association of RIG-I with unfavorable OC outcome, we determined the expression levels of checkpoint molecules 34 as well as a fate-specifying transcription factor of regulatory T cells (Tregs). 35 We found that tumors with high RIG-I expression were markedly enriched in PD-L1 (p < 0.001, Fig.…”

Explaining Pathogenicity of Congenital Zika and Guillain–Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

“…ADARs are RNA editing enzymes that deaminate adenosines (A) to produce inosines (I) within double‐stranded RNAs . These A‐to‐I changes are translated as A‐to‐G substitutions in messenger RNA (mRNA) transcripts, thereby modulating proteome diversity and expression by introducing nonsynonymous substitutions or splice site changes, and serving as a mechanism of dynamic and nuanced post‐transcriptional regulation of gene expression .…”

“…There are three mammalian ADAR loci: ADAR, ADARB1, and ADARB2 . Only ADAR and ADARB1 have proven deaminase activity, while ADARB2 is thought to play a regulatory role through competition with other ADARs for the substrate . It should be noted that the expression and editing activities of one family member can be influenced by the expression and editing activities of the other ADARs .…”