Self or Non-Self? It Is also a Matter of RNA Recognition and Editing by ADAR1

Abstract

A-to-I editing is a post-transcriptional mechanism affecting coding and non-coding dsRNAs, catalyzed by the adenosine deaminases acting on the RNA (ADAR) family of enzymes. A-to-I modifications of endogenous dsRNA (mainly derived from Alu repetitive elements) prevent their recognition by cellular dsRNA sensors, thus avoiding the induction of antiviral signaling and uncontrolled IFN-I production. This process, mediated by ADAR1 activity, ensures the activation of an innate immune response against foreign (non-self) but not self nucleic acids. As a consequence, ADAR1 mutations or its de-regulated activity promote the development of autoimmune diseases and strongly impact cell growth, also leading to cancer. Moreover, the excessive inflammation promoted by Adar1 ablation also impacts T and B cell maturation, as well as the development of dendritic cell subsets, revealing a new role of ADAR1 in the homeostasis of the immune system.

Keywords: ADAR1; IFN; RNA editing; immune system.

Figure 1

Effect of ADAR1-mediated A-to-I editing on endogenous and exogenous dsRNA. In the presence of ADAR1, endogenous dsRNA is edited (red square) and does not activate MDA5, RIG-I and PKR (homeostasis, normal tissues). In case of ADAR1 deficiency or mutation, endogenous dsRNA is not edited and recognized as non-self, as for exogenous microbial RNA, leading to IFN (IFN-I and -III) production, a strong ISG signature and uncontrolled immune response activation (chronic inflammation, autoimmune diseases). On the contrary, when ADAR1 is overexpressed, IFNs and their ISGs are dampened, limiting immune responses (tumor).