mTORC1 Links Protein Quality and Quantity Control by Sensing Chaperone Availability
mTORC1 Links Protein Quality and Quantity Control by Sensing Chaperone Availability
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DOI：
10.1074/jbc.m110.120295
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发表时间：
2010-08-27
影响因子：
4.8
通讯作者：
Patterson, Cam
中科院分区：
文献类型：
--
作者：
Qian, Shu-Bing;Zhang, Xingqian;Patterson, Cam
平衡的蛋白质合成和降解对于正常的细胞功能至关重要。蛋白质合成通过哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）与能量状态和营养水平紧密耦合。新合成多肽的质量由分子伴侣和泛素-蛋白酶体系统维持。关于细胞如何同时整合有关翻译产物的数量和质量的信息，我们知之甚少。我们证明，细胞区分中度减少蛋白质质量严重的蛋白质错误折叠使用分子伴侣差异调节mTORC 1信号。适度减少伴侣可用性增强mTORC 1信号传导，而应激诱导的伴侣能力完全耗尽抑制mTORC 1信号传导。分子伴侣调节mTORC 1组装与营养供应协调。这种机制使mTORC 1能够快速检测和响应环境线索，同时也能检测细胞内蛋白质的错误折叠。蛋白质质量和数量控制之间的紧密联系提供了一个合理的机制耦合蛋白质错误折叠与代谢失调。
Balanced protein synthesis and degradation are crucial for proper cellular function. Protein synthesis is tightly coupled to energy status and nutrient levels by the mammalian target of rapamycin complex 1 (mTORC1). Quality of newly synthesized polypeptides is maintained by the molecular chaperone and ubiquitin-proteasome systems. Little is known about how cells integrate information about the quantity and quality of translational products simultaneously. We demonstrate that cells distinguish moderate reductions in protein quality from severe protein misfolding using molecular chaperones to differentially regulate mTORC1 signaling. Moderate reduction of chaperone availability enhances mTORC1 signaling, whereas stress-induced complete depletion of chaperoning capacity suppresses mTORC1 signaling. Molecular chaperones regulate mTORC1 assembly in coordination with nutrient availability. This mechanism enables mTORC1 to rapidly detect and respond to environmental cues while also sensing intracellular protein misfolding. The tight linkage between protein quality and quantity control provides a plausible mechanism coupling protein misfolding with metabolic dyshomeostasis.