Molecular Cell
Volume 68, Issue 3, 2 November 2017, Pages 504-514.e7
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Article
m6A Facilitates eIF4F-Independent mRNA Translation

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Highlights

  • eIF4F inhibition partially represses global protein synthesis

  • Translation of non-TOP mRNAs depends on 5′ UTR N6-methyladenosine

  • ABCF1 is critical for eIF4F-independent mRNA translation

  • ABCF1 coordinates with METTL3 in m6A-facilitated mRNA translation

Summary

In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m7G) cap found on the 5′ end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The broad spectrum of eIF4F-resistant translatomes is incompatible with cap-independent translation mediated by internal ribosome entry sites (IRESs). Here, we report that N6-methyladenosine (m6A) facilitates mRNA translation that is resistant to eIF4F inactivation. Depletion of the methyltransferase METTL3 selectively inhibits translation of mRNAs bearing 5′ UTR methylation, but not mRNAs with 5′ terminal oligopyrimidine (TOP) elements. We identify ABCF1 as a critical mediator of m6A-promoted translation under both stress and physiological conditions. Supporting the role of ABCF1 in m6A-facilitated mRNA translation, ABCF1-sensitive transcripts largely overlap with METTL3-dependent mRNA targets. By illustrating the scope and mechanism of eIF4F-independent mRNA translation, these findings reshape our current perceptions of cellular translational pathways.

Keywords

translation
mRNA methylation
eIF4F
METTL3
ABCF1
stress response
epitranscriptome
cap-independent translation

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