Stress tolerance of misfolded carboxypeptidase Y requires maintenance of protein trafficking and degradative pathways.
Stress tolerance of misfolded carboxypeptidase Y requires maintenance of protein trafficking and degradative pathways.
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DOI：
10.1091/mbc.e02-11-0717
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发表时间：
2003-07
影响因子：
3.3
通讯作者：
Eric D. Spear;D. Ng
中科院分区：
文献类型：
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作者：
Eric D. Spear;D. Ng
异常折叠蛋白质的积累可导致细胞功能障碍和死亡。目前，毒性机制和细胞防御其影响仍然不完全清楚。在内质网（ER）中，由错误折叠蛋白引起的应激激活未折叠蛋白反应（UPR）。UPR是一种ER-至-核信号转导通路，其调节多种靶基因以维持细胞内稳态。我们研究了ER应激在芽殖酵母中的影响，通过表达的良好特征的错误折叠蛋白质，CPY*。通过挑战细胞在其生理极限内抵抗压力，我们表明UPR是维持蛋白质易位、糖基化、降解和运输等基本功能所必需的。在应激条件下，错误折叠蛋白质的ER相关降解（ERAD）途径是饱和的。为了维持体内平衡，依赖于UPR的“溢流”途径将多余的底物运输到液泡进行周转。这一途径的重要性，揭示了通过突变株受损的囊泡贩运过量CPY*。在野生型细胞耐受的水平下表达CPY* 对这些菌株是有毒的，尽管保留了激活UPR的能力。
The accumulation of aberrantly folded proteins can lead to cell dysfunction and death. Currently, the mechanisms of toxicity and cellular defenses against their effects remain incompletely understood. In the endoplasmic reticulum (ER), stress caused by misfolded proteins activates the unfolded protein response (UPR). The UPR is an ER-to-nucleus signal transduction pathway that regulates a wide variety of target genes to maintain cellular homeostasis. We studied the effects of ER stress in budding yeast through expression of the well-characterized misfolded protein, CPY*. By challenging cells within their physiological limits to resist stress, we show that the UPR is required to maintain essential functions including protein translocation, glycosylation, degradation, and transport. Under stress, the ER-associated degradation (ERAD) pathway for misfolded proteins is saturable. To maintain homeostasis, an "overflow" pathway dependent on the UPR transports excess substrate to the vacuole for turnover. The importance of this pathway was revealed through mutant strains compromised in the vesicular trafficking of excess CPY*. Expression of CPY* at levels tolerated by wild-type cells was toxic to these strains despite retaining the ability to activate the UPR.