Evolution of robustness to protein mistranslation by accelerated protein turnover. Adaptation to mistranslation in S. cerevisiae

Protein synthesis is affected by a variety of mRNA translational errors that promote protein aggregation, destabilize the proteome and influence organism fitness, ageing and the onset of genetic diseases. To investigate how organisms mitigate the deleterious effects of protein synthesis errors during evolution, a mutant yeast strain was engineered to translate a codon ambiguously (mistranslation), thereby overloading protein quality control pathways and disrupting cellular protein homeostasis. Such strain was used to study the capacity of the yeast genome to compensate the deleterious effects of protein mistranslation. Laboratory evolutionary experiments revealed that fitness loss due to mistranslation can be rapidly mitigated. Genomic analysis demonstrated that adaptation was primarily mediated by large-scale chromosomal duplication and deletion events, suggesting that errors during protein synthesis promote the evolution of genome architecture. Evolution increased the level of tolerance to mistranslation through up-regulation of ubiquitin-proteasome mediated protein degradation and protein synthesis. As a consequence of rapid elimination of erroneous protein products, evolution reduced the extent of toxic protein aggregation in mistranslating cells, however there was a strong evolutionary trade-off between adaptation to mistranslation and survival upon starvation: the evolved lines showed fitness defects and impaired capacity to degrade mature ribosomes upon nutrient limitation. Moreover, as a response to an enhanced energy demand of accelerated protein turnover, the evolved lines exhibited increased glucose uptake by selective duplication of hexose transporter genes. In conclusion, the adjustment of proteome homeostasis to mistranslation evolves rapidly, but this adaptation has several side-effects on cellular physiology. The data also indicates that translational fidelity and the ubiquitin-proteasome system are functionally linked to each other and may co-evolve in nature.