title: Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus infection.
abstract: The RNA-editing enzyme ADAR1 is a double-stranded RNA (dsRNA) binding protein that modifies cellular and viral RNA sequences by adenosine deamination. ADAR1 has been demonstrated to play important roles in embryonic erythropoiesis, viral response, and RNA interference. In human hepatitis virus infection, ADAR1 has been shown to target viral RNA and to suppress viral replication through dsRNA editing. It is not clear whether this antiviral effect of ADAR1 is a common mechanism in response to viral infection. Here, we report a proviral effect of ADAR1 that enhances replication of vesicular stomatitis virus (VSV) through a mechanism independent of dsRNA editing. We demonstrate that ADAR1 interacts with dsRNA-activated protein kinase PKR, inhibits its kinase activity, and suppresses the alpha subunit of eukaryotic initiation factor 2 (eIF-2alpha) phosphorylation. Consistent with the inhibitory effect on PKR activation, ADAR1 increases VSV infection in PKR+/+ mouse embryonic fibroblasts; however, no significant effect was found in PKR-/- cells. This proviral effect of ADAR1 requires the N-terminal domains but does not require the deaminase domain. These findings reveal a novel mechanism of ADAR1 that increases host susceptibility to viral infection by inhibiting PKR activation.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.forename: Graeme L
authors.initials: GL
authors.lastname: Hammond
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Yang
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D012330:RNA, Double-Stranded / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D016601:RNA-Binding Proteins; D014721:Vesicular stomatitis Indiana virus / Q000472:pathogenicity*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D019892:eIF-2 Kinase; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase