Journal
VIROLOGY
Volume 409, Issue 2, Pages 262-270Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2010.10.016
Keywords
2 '-5 ' oligoadenylate synthetase; RNase L; 2-5A; Flavivirus; RNA-protein interaction
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Funding
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI045135, AI048088]
- National Cancer Institute, National Institutes of Health [CA044059]
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Resistance to flavivirus-induced disease in mice is conferred by the autosomal gene Fly, identified as 2'-5' oligoadenylate synthetase 1b (Oas1b). Resistant mice express a full-length Oas1b protein while susceptible mice express the truncated Oas1btr. In this study, Oas1b was shown to be an inactive synthetase. Although the Oas/RNase L pathway was previously shown to have an antiviral role during flavivirus infections, Oas1b protein inhibited Oas1a in vitro synthetase activity in a dose-dependent manner and reduced 2-5A production in vivo in response to poly(I:C). These findings suggest that negative regulation of 2-5A by inactive Oas1 proteins may fine tune the RNase L response that if not tightly controlled could cause significant damage in cells. The results also indicate that flavivirus resistance conferred by Oas1b is not mediated by 2-5A. Instead, Oas1b inhibits flavivirus replication by an alternative mechanism that overrides the proviral effect of reducing 2-5A accumulation and RNase L activation. (C) 2010 Elsevier Inc. All rights reserved.
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