20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans
20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans
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DOI：
10.1096/fj.14-252189
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发表时间：
2015-02-01
期刊：
影响因子：
4.8
通讯作者：
Gonos, Efstathios S.
中科院分区：
文献类型：
--
作者：
Chondrogianni, Niki;Georgila, Konstantina;Gonos, Efstathios S.
蛋白质稳态(蛋白质稳态)是需要保存以保持生理细胞/机体平衡的结点之一。泛素蛋白酶体系统(UPS)负责去除正常和受损的蛋白质，蛋白酶体是下游的效应器。蛋白酶体是细胞内主要的蛋白水解酶，在衰老和衰老过程中功能进行性受损。尽管蛋白酶体激活在各种细胞模型中具有延缓衰老的特性，但在任何多细胞生物体中，还没有报道过同时增强20S核心蛋白酶体的内容、组装和功能的报道。因此，核心蛋白酶体调节对生物体寿命的可能影响是难以捉摸的。在这项研究中，我们已经在生物水平上实现了20S蛋白酶体的激活。我们证明了在线虫秀丽线虫中蛋白酶体水平、组装和活性的增强，导致寿命延长和对压力的抵抗力增强。我们还提供了证据表明，观察到的寿命延长依赖于Dauer形成异常/叉头盒O类(DAF-16/FOXO)、光头盒-1(SKN1)和热休克因子-1(HSF-1)因子的转录活性，这是通过调节下游长寿基因来实现的。我们进一步表明，所报道的有益影响并不是无处不在的，但它们依赖于遗传背景。最后，我们提供的证据表明，蛋白酶体核心激活可能是一种潜在的策略，可以最大限度地减少与聚集相关的疾病，如阿尔茨海默病(AD)或亨廷顿病(HD)的蛋白质稳态缺陷。综上所述，这是第一个证明在多细胞真核生物中，20S核心蛋白酶体在含量和活性方面上调都是可行的，并且这种调节反过来又促进了生物体的健康和寿命的延长。-Chondrogianni，N.，Georgila，K.，Kourtis，N.，Tavernarakis，N.，Gonos，E.S.20S蛋白酶体激活促进了秀丽线虫寿命的延长和对蛋白毒性的抵抗。
Protein homeostasis (proteostasis) is one of the nodal points that need to be preserved to retain physiologic cellular/organismal balance. The ubiquitinproteasome system(UPS) is responsible for the removal of both normal and damaged proteins, with the proteasome being the downstream effector. The proteasome is the major cellular protease with progressive impairment of function during aging and senescence. Despite the documented age-retarding properties of proteasome activation in various cellular models, simultaneous enhancement of the 20S core proteasome content, assembly, and function have never been reported in any multicellular organism. Consequently, the possible effects of the core proteasome modulation on organismal life span are elusive. In this study, we have achieved activation of the 20S proteasome at organismal level. We demonstrate enhancement of proteasome levels, assembly, and activity in the nematode Caenorhabditis elegans, resulting in life span extension and increased resistance to stress. We also provide evidence that the observed life span extension is dependent on the transcriptional activity of Dauer formation abnormal/ Forkhead box class O (DAF-16/FOXO), skinhead-1 (SKN1), and heat shock factor-1 (HSF-1) factors through regulation of downstream longevity genes. We further show that the reported beneficial effects are not ubiquitous but they are dependent on the genetic context. Finally, we provide evidence that proteasome core activation might be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation-related diseases, such as Alzheimer's disease (AD) or Huntington's disease (HD). In summary, this is the first report demonstrating that 20S core proteasome up-regulation in terms of both content and activity is feasible in a multicellular eukaryotic organism and that in turn this modulation promotes extension of organismal health span and life span.-Chondrogianni, N., Georgila, K., Kourtis, N., Tavernarakis, N., Gonos, E. S. 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans.