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A researcher’s guide to the galaxy of IRESs

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Abstract

The idea of internal initiation is frequently exploited to explain the peculiar translation properties or unusual features of some eukaryotic mRNAs. In this review, we summarize the methods and arguments most commonly used to address cases of translation governed by internal ribosome entry sites (IRESs). Frequent mistakes are revealed. We explain why “cap-independent” does not readily mean “IRES-dependent” and why the presence of a long and highly structured 5′ untranslated region (5′UTR) or translation under stress conditions cannot be regarded as an argument for appealing to internal initiation. We carefully describe the known pitfalls and limitations of the bicistronic assay and artefacts of some commercially available in vitro translation systems. We explain why plasmid DNA transfection should not be used in IRES studies and which control experiments are unavoidable if someone decides to use it anyway. Finally, we propose a workflow for the validation of IRES activity, including fast and simple experiments based on a single genetic construct with a sequence of interest.

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Abbreviations

4E-BP:

eIF4E-binding protein

CAGE:

Cap analysis of gene expression

CDS:

Coding DNA sequence

CITE:

Cap-independent translation enhancer

CrPV:

Cricket paralysis virus

eIF:

Eukaryotic translation initiation factor

EMCV:

Encephalomyocarditis virus

FMDV:

Foot and mouth decease virus

HalV:

Halastavi árva virus

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

HRV:

Human rhinovirus

IFIT:

Interferon-induced proteins with tetratricopeptide repeats

IRES:

Internal ribosome entry site

KSHV:

Kaposi's sarcoma-associated Herpes Virus

PV:

Poliovirus

RhPV:

Rhopalosiphum padi virus

RRL:

Rabbit reticulocyte lysate

SHAPE:

Selective 2′-hydroxyl acylation analyzed by primer extension

TSS:

Transcription start site

uORF:

Upstream open reading frame

UTR:

Untranslated region

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Acknowledgements

We thank Vasili Hauryliuk for critical reading of the manuscript. The work was supported by grants from Russian Science Foundation to Ivan N. Shatsky (16-14-10065) and Russian Foundation for Basic Research to Ilya M. Terenin (13-04-00903a and 16-04-0162816).

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Authors and Affiliations

  1. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119234, Russia

    Ilya M. Terenin, Victoria V. Smirnova, Dmitri E. Andreev, Sergey E. Dmitriev & Ivan N. Shatsky

  2. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119334, Russia

    Ilya M. Terenin & Sergey E. Dmitriev

  3. Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119234, Russia

    Victoria V. Smirnova

  4. Department of Biochemistry, Biological Faculty, Lomonosov Moscow State University, Moscow, 119234, Russia

    Sergey E. Dmitriev

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  1. Ilya M. Terenin
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Correspondence to Ilya M. Terenin or Ivan N. Shatsky.

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Terenin, I.M., Smirnova, V.V., Andreev, D.E. et al. A researcher’s guide to the galaxy of IRESs. Cell. Mol. Life Sci. 74, 1431–1455 (2017). https://doi.org/10.1007/s00018-016-2409-5

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