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

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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.

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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.
Akihiro Oguro

Department of Molecular Biology, The Jikei University School of Medicine, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Yoshikazu Nakamura

Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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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.