Abstract：
Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.Abbreviations: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14.
摘要：
衰老通常伴随着蛋白质稳定性的下降，表现为错误折叠的蛋白质聚集体的倾向增加，它们被蛋白质质量控制系统所阻止，如泛素-蛋白酶体系统（UPS）和巨自噬/自噬。尽管已经阐明了UPS和自噬在减缓年龄诱导的蛋白质稳定下降中的作用，关于如何以协作方式激活这些途径以延缓与蛋白质停滞相关的衰老的信息有限.这里,我们表明,使用IU1通过药理学抑制USP14(泛素特异性肽酶14)激活UPS可改善果蝇和人类细胞中由衰老或蛋白抑制应激引起的蛋白抑制和自噬下降.用IU1治疗不仅减轻了老化的果蝇飞行肌肉中聚泛素化蛋白的聚集，而且通过同时激活UPS和自噬，通过增强机车活性延长了飞行寿命。有趣的是,当蛋白酶体活性被抑制时，这种药物的作用消失了，但在Foxo突变破坏蛋白质的情况下很明显。总的来说,我们的研究结果揭示了有效改善与蛋白质紊乱相关的年龄相关病理的潜在策略。
