title: Adenosine deaminase acting on RNA 1 limits RIG-I RNA detection and suppresses IFN production responding to viral and endogenous RNAs.
abstract: 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.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Pathophysiology, Southern Medical University, Guangzhou, China 510515;
authors.forename: Peng
authors.initials: P
authors.lastname: Deng
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
authors.affiliation: Department of Immunology and Infectious Disease, SRI Biosciences, Lexington Park, MD 20653.
authors.forename: Tony
authors.initials: T
authors.lastname: Wang
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and.
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; wangq2@upmc.edu billiartr@upmc.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; wangq2@upmc.edu billiartr@upmc.edu.
authors.forename: Qingde
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000276:immunology*; D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009421:Nervous System Malformations / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000235:genetics / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases