microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site

The liver-specific microRNA-122 (miR-122) recognizes two conserved sites at the 5′ end of the hepatitis C virus (HCV) genome and contributes to stability, translation, and replication of the viral RNA. We show that stimulation of the HCV internal ribosome entry site (IRES) by miR-122 is essential fo...

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Veröffentlicht in:Nature communications 2018-07, Vol.9 (1), p.2613-14, Article 2613
Hauptverfasser: Schult, Philipp, Roth, Hanna, Adams, Rebecca L., Mas, Caroline, Imbert, Lionel, Orlik, Christian, Ruggieri, Alessia, Pyle, Anna M., Lohmann, Volker
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Sprache:eng
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Zusammenfassung:The liver-specific microRNA-122 (miR-122) recognizes two conserved sites at the 5′ end of the hepatitis C virus (HCV) genome and contributes to stability, translation, and replication of the viral RNA. We show that stimulation of the HCV internal ribosome entry site (IRES) by miR-122 is essential for efficient viral replication. The mechanism relies on a dual function of the 5′ terminal sequence in the complementary positive (translation) and negative strand (replication), requiring different secondary structures. Predictions and experimental evidence argue for several alternative folds involving the miR-binding region (MBR) adjacent to the IRES and interfering with its function. Mutations in the MBR, designed to suppress these dysfunctional structures indeed stimulate translation independently of miR-122. Conversely, MBR mutants favoring alternative folds show impaired IRES activity. Our results therefore suggest that miR-122 binding assists the folding of a functional IRES in an RNA chaperone-like manner by suppressing energetically favorable alternative secondary structures. The liver-specific microRNA-122 is an essential proviral host factor of Hepatitis C virus replication. Here the authors show that microRNA-122 functions as an RNA chaperone that guides the formation of a functional internal ribosome entry site by preventing energetically more favorable secondary structures within the HCV RNA genome.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-05053-3