A structured RNA motif locks Argonaute2:miR-122 onto the 5’ end of the HCV genome

Gebert, Luca R.; Law, Mansun; MacRae, Ian J.

doi:10.1038/s41467-021-27177-9

Title: A structured RNA motif locks Argonaute2:miR-122 onto the 5’ end of the HCV genome

Journal Article · Thu Nov 25 00:00:00 EST 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-27177-9· OSTI ID:1903874

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The Scripps Research Institute, La Jolla, CA (United States)

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.

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Research Organization:: The Scripps Research Inst., La Jolla, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); Swiss National Science Foundation (SNSF); Novartis Foundation for Medical-Biological Research; National Institutes of Health (NIH); National Cancer Institute (NCI); National Institute of General Medical Sciences

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; AC02-76SF00515; AI123365; R35GM127090; P30 GM124169-01; ACB-12002; AGM-12006; P41GM103393

OSTI ID:: 1903874

Journal Information:: Nature Communications, Vol. 12, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Title: A structured RNA motif locks Argonaute2:miR-122 onto the 5’ end of the HCV genome

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