Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae.
Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae.
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DOI：
10.1371/journal.pgen.1002253
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发表时间：
2011-09
期刊：
影响因子：
4.5
通讯作者：
Schmidt M
中科院分区：
文献类型：
--
作者：
Kruegel U;Robison B;Dange T;Kahlert G;Delaney JR;Kotireddy S;Tsuchiya M;Tsuchiyama S;Murakami CJ;Schleit J;Sutphin G;Carr D;Tar K;Dittmar G;Kaeberlein M;Kennedy BK;Schmidt M
衰老的特征是由修复和消除途径下降引起的受损细胞大分子的积累。细胞对抗毒性蛋白质聚集体的一个组成部分是保守的泛素/蛋白酶体系统（UPS）。之前的研究已经描述了百岁老人和裸鼹鼠（一种长寿啮齿动物）中蛋白酶体功能的年龄依赖性下降和寿命延长与蛋白酶体持续能力相关。然而，增强蛋白酶体功能对寿命的直接影响的证据仍然缺乏。为了确定蛋白酶体功能在酵母老化中的重要性，我们建立了一种通过操纵UPS相关转录因子Rpn 4的水平来调节UPS能力的方法。虽然缺乏RPN 4的细胞表现出非适应性蛋白酶体池减少，但UBR 2（一种调节Rpn 4周转的泛素连接酶）的丢失导致Rpn 4水平升高，从而上调UPS组分。UPS能力的增加显着提高复制寿命（RLS）和抵抗蛋白毒性应激，而UPS能力的降低具有相反的后果。尽管UPS和氧化解毒系统的紧密转录共调节，但蛋白酶体能力对寿命的影响与后者无关，因为消除氧化应激反应的关键调节因子Yap 1不会影响具有较高蛋白酶体能力的细胞的寿命延长。此外，由于蛋白酶体能力的提高导致神经退行性疾病的酵母模型中的毒性亨廷顿蛋白片段的清除率提高，我们推测观察到的寿命延长源于旧母细胞中受损蛋白的长期消除。上位性分析表明，蛋白酶体介导的寿命调制至少部分不同于饮食限制，托尔1，和Sir 2。这些研究结果表明，UPS能力决定酵母RLS的机制是不同于已知的长寿途径，并提高了干预措施，以促进增强蛋白酶体功能的可能性，将对人类的长寿和年龄相关疾病的有益影响。泛素/蛋白酶体系统（UPS）是维持细胞蛋白质稳态的机制的组成部分，并且代表真核细胞的细胞质和细胞核中特异性蛋白质降解的主要途径。它的蛋白水解能力随着年龄的增长而下降。同时，由于累积的蛋白质损伤，UPS的底物负荷在老化细胞中增加。这种不平衡被认为是经常观察到的衰老细胞中蛋白质聚集体积累的起源，并被认为有助于年龄相关的细胞功能障碍。在这项研究中，我们研究了蛋白酶体的复制寿命在酿酒酵母使用的遗传系统，允许操纵UPS丰度在转录水平上的影响。所获得的结果揭示了蛋白酶体能力和寿命之间的正相关性，在具有低蛋白酶体丰度或活性的细胞中寿命减少，并且在至少部分独立于已知酵母寿命调节途径的机制中上调UPS后寿命延长。在神经退行性疾病的酵母模型中观察到氧化和蛋白质应激耐受性以及有毒亨廷顿蛋白片段的清除的相同相关性，这表明蛋白酶体能力增加导致的寿命延长是由蛋白质稳态改善引起的。
Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS–related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans. The ubiquitin/proteasome system (UPS) is an integral part of the machinery that maintains cellular protein homeostasis and represents the major pathway for specific protein degradation in the cytoplasm and nuclei of eukaryotic cells. Its proteolytic capacity declines with age. In parallel, substrate load for the UPS increases in aging cells due to accumulated protein damage. This imbalance is thought to be an origin for the frequently observed accumulation of protein aggregates in aged cells and is thought to contribute to age-related cellular dysfunction. In this study, we investigated the impact of proteasome capacity on replicative lifespan in Saccharomyces cerevisiae using a genetic system that allows manipulation of UPS abundance at the transcriptional level. The results obtained reveal a positive correlation between proteasome capacity and longevity, with reduced lifespan in cells with low proteasome abundance or activity and strong lifespan extension upon up-regulation of the UPS in a mechanism that is at least partially independent of known yeast longevity modulating pathways. The same correlation is observed for oxidative and protein stress tolerance and clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, suggesting that lifespan extension by increased proteasome capacity is caused by improved protein homeostasis.
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