Evolution of Robustness to Protein Mistranslation by Accelerated Protein Turnover

Translational errors occur at high rates, and they influence organism viability 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). It thereby overloads the protein quality-control pathways and disrupts cellular protein homeostasis. This 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 rapidly be 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. By altering the dosages of numerous, functionally related proteins simultaneously, these genetic changes introduced large phenotypic leaps that enabled rapid adaptation to mistranslation. Evolution increased the level of tolerance to mistranslation through acceleration 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. We conclude that adjustment of proteome homeostasis to mistranslation evolves rapidly, but this adaptation has several side effects on cellular physiology. Our work also indicates that translational fidelity and the ubiquitin-proteasome system are functionally linked to each other and may, therefore, co-evolve in nature.翻译错误（translational error）发生率极高，可影响生物体存活力并诱发遗传疾病。为探究生物体在演化过程中如何缓解蛋白质合成错误（protein synthesis error）带来的有害影响，研究人员构建了一株可歧义性翻译密码子的突变酵母菌株（mutant yeast strain），该菌株会引发错译（mistranslation），进而使蛋白质质量控制通路（protein quality-control pathway）过载并扰乱细胞蛋白质稳态（cellular protein homeostasis）。本研究利用该菌株探究酵母基因组补偿蛋白质错译有害影响的能力。实验室演化实验显示，由错译导致的适合度损失（fitness loss）可被快速缓解。基因组分析表明，适应性演化主要通过大规模染色体复制与缺失（large-scale chromosomal duplication and deletion）事件介导，这提示蛋白质合成过程中的错误可推动基因组结构（genome architecture）的演化。这类遗传改变可同时改变大量功能相关蛋白质的剂量，由此产生大幅表型跃迁（phenotypic leap），使细胞能够快速适应错译环境。演化通过加速泛素-蛋白酶体介导的蛋白质降解（ubiquitin-proteasome-mediated protein degradation）与蛋白质合成过程，提升了细胞对错译的耐受水平。由于错误蛋白质产物被快速清除，演化降低了错译细胞中毒性蛋白质聚集（toxic protein aggregation）的程度。然而，对错译的适应性演化与饥饿胁迫下的生存能力存在显著演化权衡（evolutionary trade-off）：演化后的菌株出现了适合度缺陷，且在营养限制（nutrient limitation）条件下降解成熟核糖体（mature ribosome）的能力受损。此外，为响应加速蛋白质周转（protein turnover）带来的更高能量需求，演化菌株通过选择性复制己糖转运蛋白基因（hexose transporter gene）提升了葡萄糖摄取能力。综上，蛋白质组稳态（proteome homeostasis）对错译的适应性调整可快速发生，但该适应性演化会对细胞生理产生若干副作用。本研究同时表明，翻译保真度（translational fidelity）与泛素-蛋白酶体系统（ubiquitin-proteasome system）存在功能关联性，因此二者或可在自然演化过程中共演化。