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

• Published in: Immunity (Cambridge, Mass.) Vol. 43; no. 5; pp. 933 - 944
• Main Authors: Pestal, Kathleen, Funk, Cory C., Snyder, Jessica M., Price, Nathan D., Treuting, Piper M., Stetson, Daniel B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.11.2015; Elsevier Limited
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adenosine Deaminase - metabolism; Animals; Autoimmune Diseases of the Nervous System - metabolism; Autoimmunity - physiology; Cloning; DEAD-box RNA Helicases - metabolism; Deoxyribonucleic acid; DNA; Enzymes; Genes; HEK293 Cells; Humans; Interferon Type I - metabolism; Interferon-Induced Helicase, IFIH1; Mice; Nervous System Malformations - metabolism; Protein Isoforms - metabolism; RNA - metabolism; RNA Editing - physiology; RNA-Binding Proteins - metabolism; Sensors; Signal Transduction - physiology
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2015.11.001

Mutations in ADAR, which 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. [Display omitted] •ADAR1 is a specific negative regulator of the MDA5-MAVS antiviral response•A substantial fraction of ADAR1-controlled gene expression is MAVS independent•ADAR1 is essential for multi-organ development•ADAR1 isoforms independently contribute to regulation of MDA5 and developmental pathways ADAR mutations cause Aicardi-Goutières syndrome, a severe human autoimmune disease, but how ADAR1 regulates autoimmunity remains unknown. Stetson and colleagues reveal two functions for ADAR1: prevention of MDA5- and MAVS-dependent autoimmunity and control of multi-organ development.