Isoforms of RNA-Editing Enzyme ADAR1 Independently Control Nucleic Acid Sensor MDA5-Driven Autoimmunity and Multi-organ Development

Abstract

Summary Mutations in the ADAR gene that encodes the ADAR1 RNA editing enzyme cause Aicardi-Goutières Syndrome (AGS), a severe autoimmune disease associated with an aberrant type I interferon response. How ADAR1 prevents autoimmunity remains incompletely defined. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered a MDA5-MAVS-independent function for ADAR1 in the development of multiple organs. We showed that the p150 isoform of ADAR1 uniquely regulated the MDA5 pathway, whereas both the p150 and p110 isoforms contributed to development. Abrupt deletion of ADAR1 in adult mice revealed that both of these functions were required throughout life. Our findings delineate genetically separable roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations.

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

“…However, suppression of these dsRNA-dependent responses by ADAR1 remarkably was not observed with the measles C mutant (7,25,27), a mutant now understood to produce much higher amounts of viral dsRNA than either WT or the V mutant virus (23,27,64). Our results described herein, together with those of others (65)(66)(67), reveal that in the absence of ADAR1 at least some of the cytoplasmic sensors of dsRNA are also triggered by cellular (self) dsRNAs. Transcriptional profiling and pathway analyses carried out with mouse embryo cells revealed a strong association between ADAR1 catalytic deficiency and the gene expression signature of IFN-treated or virus-infected cells characteristic of RIG-I and MDA5 activation (65,68).…”

“…Among these responses is the activation of PKR and eIF2␣ phosphorylation (Fig. 3) (13, 19), and the activation of RIG-receptor signaling and enhanced IFN gene transcription (63,65,67,80). These cellular responses are suppressed by ADAR1 (7, 25, 27, 81).…”

“…Genetic disruptions of the Adar1 gene, either knocking out both p110 and p150 or disrupting only p150 alone, or the knock-in of the editing-deficient Adar1 E861A mutant, result in embryonic lethality characterized by increased cell death in the hematopoietic system and disintegration of the fetal liver (42,44,51,65). Independent roles for ADAR1 isoforms have been described, with p150 affecting the MDA5 receptor response and both p150 and p110 isoforms affecting multiorgan development in the mouse (67). ADAR1 is expressed in a broad range of different tissues in adult mice and during embryonic development (37,44,51).…”

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

“…Samhd1 −/− mice, like Rnaseh2b A174T/A174T mice, display an ISG response in the absence of detectable pathology (Behrendt et al , 2013; Rehwinkel et al , 2013). In contrast a strong ISG response in Adar1 null or editing‐deficient mice is associated with embryonic lethality (Mannion et al , 2014; Liddicoat et al , 2015; Pestal et al , 2015), and with autoinflammatory cardiomyopathy and multi‐tissue involvement in Trex1 −/− mice (Morita et al , 2004; Stetson et al , 2008; Gall et al , 2012). The variation in severity between different AGS gene mouse models remains unexplained, although it may be meaningful that mutations in human RNASEH2B are associated with the least severe disease course, with AGS onset generally in infancy, in contrast to the prenatal/neonatal onset more commonly seen in TREX1 patients (Crow et al , 2015).…”

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).…”