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ADAR1 Biology Can Hinder Effective Antiviral RNA Interference
Skyler Uhl1,2,3, Chanyong Jang4, Justin J Frere1,2,3
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Journal of Virology
|April 5, 2023
Summary
Host adenosine deaminase acting on RNA 1 (ADAR1) disrupts RNA interference (RNAi) antiviral defenses in mammals by editing viral RNA. This interference allows viruses to replicate and explains ADAR1
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Viruses evolve to evade host antiviral defenses through genetic changes or novel gene products.
- RNA interference (RNAi) is a key antiviral defense mechanism utilizing microRNAs (miRNAs) for gene silencing.
- Previous studies showed positive-strand RNA viruses, but not negative-strand RNA viruses, escape miRNA targeting via recombination.
Purpose of the Study:
- To investigate viral evasion mechanisms against RNA interference (RNAi)-based antiviral defenses in mammalian cells.
- To determine the role of host adenosine deaminase acting on RNA 1 (ADAR1) in viral escape from miRNA-mediated silencing.
Main Methods:
- Established a mammalian cell system using recombinant Sendai virus targeted by endogenous miRNAs.
- Analyzed viral escape mechanisms over extended periods, focusing on the involvement of ADAR1.
- Expressed ADAR1 in Nicotiana benthamiana to assess its impact on endogenous RNAi pathways.
Main Results:
- Extended incubation allowed miRNA-targeted Sendai virus to escape, mediated by host ADAR1.
- ADAR1 editing disrupted miRNA-silencing motifs on viral RNA, hindering RNAi effectiveness.
- Exogenous ADAR1 expression in plants suppressed endogenous RNAi, confirming its inhibitory role.
Conclusions:
- ADAR1 actively diminishes the efficacy of RNAi antiviral defenses in mammals.
- ADAR1's interference with RNAi may explain its absence in species relying heavily on this defense system.
- ADAR1 plays a significant role in viral evasion and sheds light on the evolution of antiviral strategies.
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