Translation initiation by the hepatitis C virus IRES requires eIF1A and ribosomal complex remodeling

  1. Zane A Jaafar
  2. Akihiro Oguro
  3. Yoshikazu Nakamura
  4. Jeffrey S Kieft  Is a corresponding author
  1. Denver School of Medicine, University of Colorado, Aurora, United States
  2. The Jikei University School of Medicine, Japan
  3. The University of Tokyo, Japan

Abstract

Internal ribosome entry sites (IRESs) are important RNA-based translation initiation signals, critical for infection by many pathogenic viruses. The hepatitis C virus (HCV) IRES is the prototype for the type 3 IRESs and is also invaluable for exploring principles of eukaryotic translation initiation, in general. Current mechanistic models for the type 3 IRESs are useful but they also present paradoxes, including how they can function both with and without eukaryotic initiation factor (eIF) 2. We discovered that eIF1A is necessary for efficient activity where it stabilizes tRNA binding and inspects the codon-anticodon interaction, especially important in the IRES' eIF2-independent mode. These data support a model in which the IRES binds preassembled translation preinitiation complexes and remodels them to generate eukaryotic initiation complexes with bacterial-like features. This model explains previous data, reconciles eIF2-dependent and -independent pathways, and illustrates how RNA structure-based control can respond to changing cellular conditions.

Article and author information

Author details

  1. Zane A Jaafar

    Department of Biochemistry and Molecular Genetics, Denver School of Medicine, University of Colorado, Aurora, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Akihiro Oguro

    Department of Molecular Biology, The Jikei University School of Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Yoshikazu Nakamura

    Institute of Medical Science, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeffrey S Kieft

    Department of Biochemistry and Molecular Genetics, Denver School of Medicine, University of Colorado, Aurora, Aurora, United States
    For correspondence
    jeffrey.kieft@ucdenver.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3718-1891

Funding

National Institutes of Health (GM081346)

  • Jeffrey S Kieft

Howard Hughes Medical Institute (Early Career Scientist Award)

  • Jeffrey S Kieft

National Institutes of Health (GM118070)

  • Jeffrey S Kieft

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Rachel Green, Johns Hopkins School of Medicine, United States

Publication history

  1. Received: September 2, 2016
  2. Accepted: December 22, 2016
  3. Accepted Manuscript published: December 23, 2016 (version 1)
  4. Version of Record published: January 16, 2017 (version 2)

Copyright

© 2016, Jaafar et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Zane A Jaafar
  2. Akihiro Oguro
  3. Yoshikazu Nakamura
  4. Jeffrey S Kieft
(2016)
Translation initiation by the hepatitis C virus IRES requires eIF1A and ribosomal complex remodeling
eLife 5:e21198.
https://doi.org/10.7554/eLife.21198

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