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TORC1‐mediated sensing of chaperone activity alters glucose metabolism and extends lifespan

机译:TORC1介导的伴侣活性检测可改变葡萄糖代谢并延长寿命

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Summary Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activity and consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age-related diseases.
机译:发明内容正常细胞功能所需的蛋白质质量控​​制机制包括与蛋白质生产和维持有关的多种功能。但是,蛋白稳态和代谢网络之间的通讯及其潜在机制仍然难以捉摸。在这里,我们报告说,TORP1通过Hsp82的活性增强了伴侣的活性,从而改善了蛋白稳态。伴侣蛋白的富集会降低Hsp82的水平,从而使TORC1失活并导致Snf1 / AMPK的激活,而与葡萄糖的可用性无关。这种机制最终导致酵母复制寿命(RLS)的延长,而后者完全依赖于TORC1失活和Snf1 / AMPK激活。具体来说,我们将耗氧量确定为Snf1激活的下游效应,负责整个RLS扩展。我们的结果为蛋白稳态在衰老中的作用建立了新的范例:错误折叠的蛋白质水平的调节可影响细胞的代谢功能以及线粒体的活性,从而改变寿命。所描述的机制有望为研究衰老和与年龄有关的疾病开辟新的途径。

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