Key result
Host engineering of Saccharomyces cerevisiae increases CrPV IRES-mediated translation ~10-fold versus the parental strain.
Why the study?
The cricket paralysis virus IRES shows very low activity in Saccharomyces cerevisiae, limiting its broader utility despite extensive structural and biochemical studies.
Multilayer host engineering in yeast can significantly enhance CrPV IRES-mediated translation, providing a framework for noncanonical translation engineering in synthetic biology.
May enhance yeast IRES tools; leaves open mammalian validation before any therapeutic use.
Internal ribosome entry sites (IRESs) provide compact RNA elements for noncanonical translation and hold promise as building blocks for RNA-based regulation in synthetic biology. However, the cricket paralysis virus (CrPV) IRES shows very low activity in Saccharomyces cerevisiae, limiting its broader utility despite extensive structural and biochemical studies. Here we report a yeast engineering strategy that enhances CrPV IRES-mediated translation by combining host modifications at three mechanistically distinct levels: translation initiation, tRNA modification, and mRNA stability. A reporter-based screen revealed host factors that influence IRES activity and uncovered a trade-off between IRES stimulation and maintenance of cap-dependent translation required for growth. Stepwise integration of nonsense-mediated decay deficiency, a tad3 temperature-sensitive allele, and wild-type eIF4E overexpression yielded a strain with up to an order-of-magnitude increase in reporter output compared with that of the parental strain. These results establish a proof-of-principle framework for host engineering of noncanonical translation.
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Cao et al. (2026) studied this question. Host engineering (nonsense-mediated decay deficiency, tad3 temperature-sensitive allele, and wild-type eIF4E overexpression) vs. Parental strain was evaluated on CrPV IRES-mediated translation (reporter output) (up to an order-of-magnitude increase). Stepwise host engineering of Saccharomyces cerevisiae yielded a strain with up to an order-of-magnitude increase in CrPV IRES-mediated translation reporter output compared with the parental strain.
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