Coordinated regulation of protein synthesis and degradation by mTORC1

摘要

Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. Mechanistic target of rapa-mycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis. Here we show that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NRF1;also known as NFE2L1).Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response to growth factors or feeding resulted in increased NRF1 expression in cells and tissues. We find that this NRF1 -dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. Therefore, mTORC1 signalling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.%细胞连续监测生长机会。当条件有利时，mTOR信号传导通道被激话，刺激氨基酸等营养成分向蛋白质等细胞构造单元转化。然而，Brendan Manning及同事报告说,同一信号传导通道也刺激蛋白降解：在mTORC1的下游，转录因子NRF1变得活跃，诱导编码蛋白酶体亚单元的基因的表达，提高活跃蛋白酶体的水平，同时刺激蛋白质周转。但同时既刺激蛋白合成又刺激蛋白降解有什么道理呢？作者发现，由mTOR通道通过蛋白降解生成的氨基酸会促进新蛋白的合成。