Adenosine deaminase acting on RNA 1 limits RIG-I RNA detection and suppresses IFN production responding to viral and endogenous RNAs

• Published in: The Journal of immunology (1950) Vol. 193; no. 7; pp. 3436 - 3445
• Main Authors: Yang, Shengyong, Deng, Peng, Zhu, Zhaowei, Zhu, Jianzhong, Wang, Guoliang, Zhang, Liyong, Chen, Alex F, Wang, Tony, Sarkar, Saumendra N, Billiar, Timothy R, Wang, Qingde
• Format: Journal Article
• Language: English
• Published: United States 01.10.2014
• Subjects: Adenosine Deaminase - genetics; Adenosine Deaminase - immunology; Animals; Autoimmune Diseases of the Nervous System - genetics; Autoimmune Diseases of the Nervous System - immunology; Autoimmune Diseases of the Nervous System - pathology; DEAD Box Protein 58; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - immunology; DEAD-box RNA Helicases - metabolism; Gene Knockdown Techniques; HEK293 Cells; Humans; Interferon Type I - genetics; Interferon Type I - immunology; Mice; Mice, Knockout; Nervous System Malformations - genetics; Nervous System Malformations - immunology; Nervous System Malformations - pathology; Receptors, Immunologic; RNA, Viral - genetics; RNA, Viral - immunology; RNA-Binding Proteins; Sendai virus - genetics; Sendai virus - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1401136

Type I IFNs play central roles in innate immunity; however, overproduction of IFN can lead to immunopathology. In this study, we demonstrate that adenosine deaminase acting on RNA 1 (ADAR1), an RNA-editing enzyme induced by IFN, is essential for cells to avoid inappropriate sensing of cytosolic RNA in an inducible knockout cell model-the primary mouse embryo fibroblast derived from ADAR1 lox/lox and Cre-ER mice as well as in HEK293 cells. ADAR1 suppresses viral and cellular RNA detection by retinoic acid-inducible gene I (RIG-I) through its RNA binding rather than its RNA editing activity. dsRNA binds to both ADAR1 and RIG-I, but ADAR1 reduces RIG-I RNA binding. In the absence of ADAR1, cellular RNA stimulates type I IFN production without viral infection or exogenous RNA stimulation. Moreover, we showed in the ADAR1-inducible knockout mice that ADAR1 gene disruption results in high-level IFN production in neuronal tissues-the hallmark of Aicardi-Goutières syndrome, a heritable autoimmune disease recently found to be associated with ADAR1 gene mutations. In summary, this study found that ADAR1 limits cytosolic RNA sensing by RIG-I through its RNA binding activity; therefore, ADAR1 suppresses type I IFN production stimulated by viral and cellular RNAs. These results explain why loss of ADARA1 causes IFN induction and also indicates a mechanism for the involvement of ADAR1 in autoimmune diseases such as Aicardi-Goutières syndrome.