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A newly discovered function for RNase L in regulating translation termination

Nature Structural & Molecular Biology volume 12, pages 505–512 (2005)Cite this article

Abstract

The antiviral and antiproliferative effects of interferons are mediated in part by the 2′-5′ oligoadenylate–RNase L RNA decay pathway. RNase L is an endoribonuclease that requires 2′-5′ oligoadenylates to cleave single-stranded RNA. In this report we present evidence demonstrating a role for RNase L in translation. We identify and characterize the human translation termination factor eRF3/GSPT1 as an interacting partner of RNase L. We show that interaction of eRF3 with RNase L leads to both increased translation readthrough efficiency at premature termination codons and increased +1 frameshift efficiency at the antizyme +1 frameshift site. On the basis of our results, we present a model describing how RNase L is involved in regulating gene expression by modulating the translation termination process.

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Figure 1: Purification and identification of an RNase L-binding protein as eRF3/GSPT1.
Figure 2: Direct interaction between eRF3/GSPT1 and RNase L recombinant proteins.
Figure 3: Activation of RNase L by 2-5A3 increases the readthrough in rabbit reticulocyte lysate (RRL).
Figure 4: Human recombinant RNase L increases the readthrough in RRL.
Figure 5: Ribosomal readthrough is increased only in the presence of 2-5A trimer (2-5A3).
Figure 6: RNase L mediates antizyme +1 frameshifting induced by IFNα.
Figure 7: Model for the mechanism of action of RNase L in translation termination.

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Acknowledgements

We thank F. Martin, O. Rouquier and D. Pappin for their help at the different steps of eRF3 protein purification and sequencing, A. Zhou for the gift of the Rnasel+/+ and Rnasel−/− mouse embryonic fibroblasts, J. Atkins for the gift of the antizyme dual luciferase plasmids and the members of the Peltz laboratory for helpful comments and critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (GM48631, AI057596) to S.W.P. and from the Association pour la Recherche contre le Cancer (4731) and La Ligue Contre le Cancer (Comités de l'Hérault et des Pyrénées-Orientales) for C.B. F.L.R. was partially funded by a postdoctoral award from the Philippe Foundation.

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Authors and Affiliations

  1. Department of Molecular Genetics, Microbiology & Immunology, UMDNJ–Robert Wood Johnson Medical School, Piscataway, 08854, New Jersey, USA

    Florence Le Roy, Joseph P Dougherty & Stuart W Peltz

  2. Groupe d'Etude des Transcriptomes, UPR CNRS 1142, Institut de Génétique Humaine, 141 Rue de la Cardonille, Montpellier, 34396 Cedex 5, France

    Tamim Salehzada & Catherine Bisbal

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Correspondence to Catherine Bisbal or Stuart W Peltz.

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Roy, F., Salehzada, T., Bisbal, C. et al. A newly discovered function for RNase L in regulating translation termination. Nat Struct Mol Biol 12, 505–512 (2005). https://doi.org/10.1038/nsmb944

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