eIF4A1-dependent mRNAs employ purine-rich 5’UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation

Schmidt, T. et al. (2023) eIF4A1-dependent mRNAs employ purine-rich 5’UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation. Nucleic Acids Research, 51(4), pp. 1859-1879. (doi: 10.1093/nar/gkad030) (PMID:36727461) (PMCID:PMC9976904)

Abstract

Altered eIF4A1 activity promotes translation of highly structured, eIF4A1-dependent oncogene mRNAs at root of oncogenic translational programmes. It remains unclear how these mRNAs recruit and activate eIF4A1 unwinding specifically to facilitate their preferential translation. Here, we show that single-stranded RNA sequence motifs specifically activate eIF4A1 unwinding allowing local RNA structural rearrangement and translation of eIF4A1-dependent mRNAs in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain AG-rich motifs within their 5’UTR which specifically activate eIF4A1 unwinding of local RNA structure to facilitate translation. This mode of eIF4A1 regulation is used by mRNAs encoding components of mTORC-signalling and cell cycle progression, and renders these mRNAs particularly sensitive to eIF4A1-inhibition. Mechanistically, we show that binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1 with eIF4A1 subunits performing distinct enzymatic activities. Our structural data suggest that RNA-binding of multimeric eIF4A1 induces conformational changes in the RNA resulting in an optimal positioning of eIF4A1 proximal to the RNA duplex enabling efficient unwinding. Our data proposes a model in which AG-motifs in the 5’UTR of eIF4A1-dependent mRNAs specifically activate eIF4A1, enabling assembly of the helicase-competent multimeric eIF4A1 complex, and positioning these complexes proximal to stable localised RNA structure allowing ribosomal subunit scanning.

• Item Type: Articles
• Additional Information: The authors would like to thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196 and A31287).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Munro, Dr June and McGhee, Dr Ewan and Dąbrowska, Adrianna and Wilczynska, Dr Ania and Zanivan, Professor Sara and Le Quesne, Professor John and Waldron, Dr Joseph and Koulouras, Mr Grigorios and Huang, Professor Danny and Gabrielsen, Dr Mads and Bushell, Professor Martin and Carlin, Dr Leo
• Authors: Schmidt, T., Dąbrowska, A., Waldron, J. A., Hodge, K., Koulouras, G., Gabrielsen, M., Munro, J., Tack, D. C., Harris, G., McGhee, E., Scott, D., Carlin, L. M., Huang, D., Le Quesne, J., Zanivan, S., Wilczynska, A., and Bushell, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nucleic Acids Research
• Publisher: Oxford University Press
• ISSN: 0305-1048
• ISSN (Online): 1362-4962
• Published Online: 02 February 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Nucleic Acids Research 51(4):1859–1879
• Publisher Policy: Reproduced under a Creative Commons License