RNA polymerase III limits longevity downstream of TORC1.
RNA polymerase III limits longevity downstream of TORC1.
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DOI：
10.1038/nature25007
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发表时间：
2017-12-14
期刊：
影响因子：
64.8
通讯作者：
Alic N
中科院分区：
文献类型：
--
作者：
Filer D;Thompson MA;Takhaveev V;Dobson AJ;Kotronaki I;Green JWM;Heinemann M;Tullet JMA;Alic N
三种不同的RNA聚合酶(POL)在真核细胞中转录不同类别的基因。POL III是一种必需的、在进化上保守的酶，它能产生短的非编码RNA，包括转移RNA(TRNAs)和5S核糖体RNA(RRNA)。历史上对蛋白质编码基因转录的关注，使得POLIII在生物体生理学中的作用相对未被探索。Pol III活性的重要调节因子雷帕霉素激酶复合体靶标1(TORC1)是一个重要的长寿决定因素，提出了Pol III参与衰老的问题。在这里，我们展示了Pol III限制了TORC1下游的寿命。我们发现，POL III的减少延长了酵母的时间寿命和蠕虫和苍蝇的有机寿命。抑制成虫或苍蝇肠道中的Pol III活性足以延长寿命，而在果蝇中，可以通过抑制Pol III特别是肠道干细胞(ISCs)来实现长寿。长寿表型与年龄相关的肠道病理改善和功能衰退、抑制蛋白质合成和提高对蛋白静态应激的耐受性有关。重要的是，Pol III在TORC1下游发挥作用，延长寿命，限制成年肠道中的Pol III活性可实现全身抑制TORC1的全部长寿益处。因此，POL III是这一关键的长寿营养信号网络的关键输出；POL III的促生长、合成代谢活性介导了TORC1加速衰老。POL III的进化保守性肯定了它作为治疗靶点的潜力。
Three distinct RNA polymerases (Pols) transcribe different classes of genes in the eukaryotic nucleus. Pol III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including transfer RNAs (tRNAs) and 5S ribosomal RNA (rRNA). Historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. The prominent regulator of Pol III activity, Target of Rapamycin kinase Complex 1 (TORC1), is an important longevity determinant, raising the question of Pol III’s involvement in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting Pol III activity in the adult worm or fly gut is sufficient to extend lifespan, and in flies, longevity can be achieved by Pol III inhibition specifically in the intestinal stem cells (ISCs). The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Importantly, Pol III acts downstream of TORC1 for lifespan and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal output of this key nutrient signalling network for longevity; Pol III’s growth-promoting, anabolic activity mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.
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