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

Philipp Schult, Hanna Roth, Rebecca L. Adams, Caroline Mas, Lionel Imbert, Christian Orlik, Alessia Ruggieri, Anna M. Pyle and Volker Lohmann ()
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Philipp Schult: University of Heidelberg
Hanna Roth: University of Heidelberg
Rebecca L. Adams: Yale University
Caroline Mas: University Grenoble Alpes, CNRS, CEA, IBS, 71 Avenue des Martyrs, CS 10090
Lionel Imbert: University Grenoble Alpes, CNRS, CEA, IBS, 71 Avenue des Martyrs, CS 10090
Christian Orlik: University of Heidelberg
Alessia Ruggieri: University of Heidelberg
Anna M. Pyle: Yale University
Volker Lohmann: University of Heidelberg

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05053-3

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