Exploring the targeting spectrum of rocaglates among eIF4A homologs
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Date
2023-06
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Published version
OA Version
Citation
S.K. Naineni, R. Cencic, F. Robert, L.E. Brown, M. Haque, J. Scott-Talib, P. Sénéchal, T.M. Schmeing, J.A. Porco, J. Pelletier. 2023. "Exploring the targeting spectrum of rocaglates among eIF4A homologs." RNA: A publication of the RNA Society, Volume 29, Issue 6, pp.826-835. https://doi.org/10.1261/rna.079318.122
Abstract
Inhibition of eukaryotic translation initiation through unscheduled RNA clamping of the DEAD-box (DDX) RNA helicases eIF4A1 and eIF4A2 has been documented for pateamine A (PatA) and rocaglates-two structurally different classes of compounds that share overlapping binding sites on eIF4A. Clamping of eIF4A to RNA causes steric blocks that interfere with ribosome binding and scanning, rationalizing the potency of these molecules since not all eIF4A molecules need to be engaged to elicit a biological effect. In addition to targeting translation, PatA and analogs have also been shown to target the eIF4A homolog, eIF4A3-a helicase necessary for exon junction complex (EJC) formation. EJCs are deposited on mRNAs upstream of exon-exon junctions and, when present downstream from premature termination codons (PTCs), participate in nonsense-mediated decay (NMD), a quality control mechanism aimed at preventing the production of dominant-negative or gain-of-function polypeptides from faulty mRNA transcripts. We find that rocaglates can also interact with eIF4A3 to induce RNA clamping. Rocaglates also inhibit EJC-dependent NMD in mammalian cells, but this does not appear to be due to induced eIF4A3-RNA clamping, but rather a secondary consequence of translation inhibition incurred by clamping eIF4A1 and eIF4A2 to mRNA.
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© 2023 Naineni et al. This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution NonCom-mercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.