ADAR1, inosine and the immune sensing system: distinguishing self from non‐self

Abstract

The conversion of genomically encoded adenosine to inosine in dsRNA is termed as A-to-I RNA editing. This process is catalyzed by two of the three mammalian ADAR proteins (ADAR1 and ADAR2) both of which have essential functions for normal organismal homeostasis. The phenotype of ADAR2 deficiency can be primarily ascribed to a lack of site-selective editing of a single transcript in the brain. In contrast, the biology and substrates responsible for the Adar1(-/-) phenotype have remained more elusive. Several recent studies have identified that a feature of absence or reductions of ADAR1 activity, conserved across human and mouse models, is a profound activation of interferon-stimulated gene signatures and innate immune responses. Further analysis of this observation has lead to the conclusion that editing by ADAR1 is required to prevent activation of the cytosolic innate immune system, primarily focused on the dsRNA sensor MDA5 and leading to downstream signaling via MAVS. The delineation of this mechanism places ADAR1 at the interface between the cells ability to differentiate self- from non-self dsRNA. Based on MDA5 dsRNA recognition requisites, the mechanism indicates that the type of dsRNA must fulfil a particular structural characteristic, rather than a sequence-specific requirement. While additional studies are required to molecularly verify the genetic model, the observations to date collectively identify A-to-I editing by ADAR1 as a key modifier of the cellular response to endogenous dsRNA.

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

“…For example, suppressor of cytokine signaling proteins 1 (SOCS1) inhibits cytokineinduced activation of the JAK family (12), protein kinase D2 (PKD2) promotes IFNAR1 ubiquitination and degradation to limit IFN-I signaling (13)(14)(15), and some of ISG-encoded proteins inhibit the recruitment of JAK to IFN-I receptors (16). Recently, adenosine deaminase acting on RNA 1 (ADAR1) has attracted much attention because of its important negative regulatory effect on IFN-I production and subsequent IFN-I-activated pathways (9,(17)(18)(19).…”

“…ADAR1 deficiency has recently been shown to be associated with aberrant organ development and severe autoimmune diseases. Mouse embryos with an editing-deficient knockin mutation of ADAR1 died at embryonic day 13.5 (18). Loss of ADAR1 results in increased IFN␣/␤ production and global up-regulation of IFN-inducible transcripts and therefore leads to rapid apoptosis of hematopoietic stem cells (9).…”

Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases

“…Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated protein 5 (MDA5) and RIG-I, are cytosolic RNA surveillance machineries that screen for pathogenic material. Both these RLRs interact with the mitochondrial activation signaling (MAVS) protein, ultimately activating transcription factors that initiate the expression of immune response genes, ranging from interferon (IFN) to antiviral genes [22]. …”

“…Yet, the largest effect was seen in Mavs −/− : Adar1 −/− double knockouts [31]. In hematopoietic stem (HSC) and progenitor (HPC) cells, MDA5 is the key receptor that detects the presence of unedited dsRNA [22]. ADAR1 may suppress autoimmune responses in HSCs and/or HPCs by editing endogenous dsRNA, such that the excess of unedited dsRNA in ADAR1’s absence results in stem cell apoptosis.…”

Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures

“…25,26 Normal ADAR1 activity would create multiple IU mismatches in these RNAs, preventing them from binding to the cytosolic dsRNA sensor IFIH1 (also known as MDA5). 26,27 While AGS has also been linked to mutations in the TREX1, RNASEH2A, RNASEH2B RNASEH2C, SAMHD1 and IFIH genes, 22 this review will focus on AGS-causing mutations mapped to the ADAR1 deaminase domain and the likely consequences of these mutations on RNA recognition by the deaminase domain. There are currently no structures of ADAR1 available.…”