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

Simple Summary A fundamental feature of innate immune cells is to detect the presence of non-self, such as potentially harmful nucleic acids, by germline-encoded specialized receptors called pattern recognition receptors (PRRs). ADAR1 is one key enzyme avoiding aberrant type I interferon (IFN-I) production and immune cell activation by the conversion of adenosine to inosine (A-to-I) in double-stranded RNA (dsRNA) structures that arise in self mRNA containing specific repetitive elements. This review intends to give an up-to-date and detailed overview of the ADAR1-mediated ability to modulate the immune response in autoimmune diseases and cancer progression. 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.