The N-terminal domain of Eukaryotic Initiation Factor 4B Drives Yeast Translational Control in Response to Urea

Abstract

The yeast eukaryotic initiation factor 4B binds the 40S subunit in translation preinitiation complexes (PICs), promoting mRNA binding. Recent evidence suggests mRNAs have variable dependence on eIF4B, suggesting this factor could promote changes in mRNA selection to adapt to stressors.However, the importance of eIF4B and its constituent domains for mRNA selection under diverse cellular and environmental conditions remain undefined. Here we compared the effects of disrupting eIF4B RNA-and ribosome-binding under ~1400 growth conditions. The RNA-Recognition Motif (RRM) was dispensable for stress responses, but ribosome binding by the N-terminal Domain (NTD) promoted growth in response to various stressors. In particular, the NTD conferred a strong growth advantage in the presence of urea. Ribosome profiling revealed that the NTD promoted translation of mRNAs with long and highly structured 5-prime untranslated regions, both with and without urea exposure. Because these changes required 40S binding, our results suggest eIF4B regulates mRNA loading and scanning as a part of the PIC, rather than by activating mRNPs prior to ribosome binding. Furthermore, our data indicate the yeast response to urea includes a translational component, driven by translation of mRNAs encoding proteins associated with the cellular periphery, suggesting general eIFs can promote diverse cellular responses.

Robust eIF4B levels undermine invasive growth and immune evasion mechanisms in murine triple negative breast cancer models

“…eIF4B activity in particular is modulated by numerous cancer-relevant kinases, including p70/S6K (26)(27)(28). Recently, instances of collective and individual up-regulation of eIF4A, eIF4B, and eIF4E have been reported in cancers (29)(30)(31) with over-expression being associated with poor prognosis and metastatic disease (3). One study in particular noted this linkage for patients with endocrine receptor-negative breast cancer (9).…”