| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Sarkar, Saumendra N. Billiar, Timothy R. Wang, Qingde Chen, Alex F. Wang, Guoliang Zhang, Liyong Wang, Tony Zhu, Jianzhong Yang, Shengyong Zhu, Zhaowei Deng, Peng |
| Description |
Author Affiliation: Yang S ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Deng P ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Zhu Z ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Zhu J ( University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Wang G ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Zhang L ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Chen AF ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Wang T ( Department of Immunology and Infectious Disease, SRI Biosciences, Lexington Park, MD 20653.); Sarkar SN ( University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Billiar TR ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213); Wang Q ( Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213) |
| 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. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1401136 |
| Journal |
The Journal of Immunology |
| Issue Number |
7 |
| Volume Number |
193 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2014-10-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Adenosine Deaminase Immunology Dead-box Rna Helicases Metabolism Interferon Type I Rna, Viral Sendai Virus Genetics Animals Autoimmune Diseases Of The Nervous System Pathology Gene Knockdown Techniques Hek293 Cells Mice Mice, Knockout Nervous System Malformations Rna-binding Proteins Research Support, N.i.h., Extramural Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
