Ubc9 auto-sumoylation-associated changes in the genome-wide pattern of SUMO enrichment.

Calorie restriction (CR) provides anti-aging benefits through diverse processes, such as reduced metabolism and growth and increased mitochondrial activity. Although controversy still exists regarding CR-mediated lifespan effects, many researchers are seeking interventions that mimic the effects of CR. Yeast has proven to be a useful model system for aging studies, including CR effects. We report here that yeast adapted through in vitro evolution to the severe cellular stress caused by loss of the Ulp2 SUMO-specific protease exhibit both enhanced growth rates and replicative lifespan, and they have altered gene expression profiles similar to those observed in CR. Notably, in certain evolved ulp2Δ lines, a dramatic increase in the auto-sumoylation of Ubc9 E2 SUMO-conjugating enzyme results in altered regulation of multiple targets involved in energy metabolism and translation at both transcriptional and post-translational levels. This increase is essential for the survival of aged cells and CR-mediated lifespan extension. Thus, we suggest that high Ubc9 auto-sumoylation exerts potent anti-aging effects by promoting efficient energy metabolism-driven improvements in cell replication abilities. This potential could be therapeutically explored for the development of novel CR-mimetic strategies.热量限制（Calorie restriction, CR）可通过多种途径发挥抗衰老益处，包括减缓代谢与生长、增强线粒体活性。尽管CR介导的寿命效应仍存在争议，但诸多研究者正致力于探寻可模拟CR作用的干预手段。酵母已被证实是衰老研究（包括CR效应研究）的实用模型系统。本文报道，经体外进化以适应Ulp2 SUMO特异性蛋白酶（Ulp2 SUMO-specific protease）缺失所引发的严重细胞应激的酵母菌株，其生长速率与复制寿命均显著提升，且基因表达谱发生改变，与CR条件下观测到的特征相似。值得注意的是，在部分经过进化的ulp2Δ菌株中，Ubc9 E2 SUMO结合酶（Ubc9 E2 SUMO-conjugating enzyme）的自动SUMO化修饰水平显著升高，导致能量代谢与蛋白质翻译过程相关的多个靶标在转录及翻译后水平的调控模式发生改变。这一修饰增强对于衰老细胞的存活以及CR介导的寿命延长均不可或缺。据此我们提出，高水平的Ubc9自动SUMO化修饰可通过促进高效能量代谢驱动的细胞复制能力提升，发挥强效抗衰老作用。这一潜在机制可为新型CR模拟策略的开发提供治疗学探索方向。