Abstract
microRNAs (miRNAs) form regulatory networks in metazoans. Viruses engage miRNA networks in numerous ways, with Flaviviridae members exploiting direct interactions of their RNA genomes with host miRNAs. For hepatitis C virus (HCV), binding of liver-abundant miR-122 stabilizes the viral RNA and regulates viral translation. Here, we investigate the structural basis for these activities, taking into consideration that miRNAs function in complex with Argonaute (Ago) proteins. The crystal structure of the Ago2:miR-122:HCV complex reveals a structured RNA motif that traps Ago2 on the viral RNA, masking its 5’ end from enzymatic attack. The trapped Ago2 can recruit host factor PCBP2, implicated in viral translation, while binding of a second Ago2:miR-122 competes with PCBP2, creating a potential molecular switch for translational control. Combined results reveal a viral RNA structure that modulates Ago2:miR-122 dynamics and repurposes host proteins to generate a functional analog of the mRNA cap-binding complex.
Highlights
IntroductionViruses engage miRNA networks in numerous ways, with Flaviviridae members exploiting direct interactions of their RNA genomes with host miRNAs. For hepatitis C virus (HCV), binding of liver-abundant miR122 stabilizes the viral RNA and regulates viral translation
The most direct, yet poorly understood, mechanisms involve binding of host miRNAs to genomes of single-stranded RNA viruses of the Flaviviridae family: HCV8,9, BVDV10, and ZIKV11 exploit host miRNAs to increase viral fitness through direct interactions with regions within their RNA genomes rich with secondary structure
The conserved SL1 within Site-1 is necessary for Ago2:miR-122-mediated protection of hepatitis C virus (HCV) RNA from XRN1 and calf intestine alkaline phosphatase (CIP)
Summary
Viruses engage miRNA networks in numerous ways, with Flaviviridae members exploiting direct interactions of their RNA genomes with host miRNAs. For hepatitis C virus (HCV), binding of liver-abundant miR122 stabilizes the viral RNA and regulates viral translation. Combined results reveal a viral RNA structure that modulates Ago2:miR-122 dynamics and repurposes host proteins to generate a functional analog of the mRNA cap-binding complex. The most direct, yet poorly understood, mechanisms involve binding of host miRNAs to genomes of single-stranded RNA viruses of the Flaviviridae family: HCV (miR-122)[8,9], BVDV (miR-17)[10], and ZIKV (miR-21)[11] exploit host miRNAs to increase viral fitness through direct interactions with regions within their RNA genomes rich with secondary structure. Stabilization of HCV RNA was reported through two tandem miR-122 complementary sites at the very 5’ end of the viral genome[8,9], and involves the host protein Argonaute[2] (Ago2)[14]
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