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Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis.

自噬 细胞生物学 未折叠蛋白反应 程序性细胞死亡 自噬体 蛋白酶体 溶酶体 蛋白质降解 蛋白质稳态 细胞质 生物 泛素 平衡 癌细胞 细胞应激反应 坏死性下垂 细胞 化学 细胞凋亡 内质网 生物化学 癌症 战斗或逃跑反应 遗传学 基因
作者
Doris M. Benbrook,Aideen Long
出处
期刊:PubMed 卷期号:34 (3): 286-97 被引量:107
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摘要

A single cell has the potential to kill an entire human being. Efforts to cure cancer are limited by survival of individual cancer cells despite immune surveillance and toxic therapies. Understanding the intricate network of pathways that maintain cellular homeostasis and mediate stress response or default into cell death is critical to the development of strategies to eradicate cancer. Autophagy, proteasomal degradation and the unfolded protein response (UPR) are cellular pathways that degrade and recycle excess or damaged proteins to maintain cellular homeostasis and survival. This review will discuss autophagy and how it is integrated with proteasomal degradation and UPR to govern cell fate through restoration of cellular homeostasis or default into the apoptotic cell death pathway. The first response of autophagy is macroautophagy, which sequesters cytoplasm including organelles inside double-membraned autophagosome vesicles that fuse with lysosomes to degrade and recycle the contents. Ubiquitination patterns on proteins targeted for degradation determine whether adapter proteins will bring them to developing autophagosomes or to proteasomes. Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor. These two processes and the lesser understood microautophagy, which involves direct engulfment of proteins into lysosomes, occur at basal and induced levels. Insufficient proteasome function or ER stress induction of UPR can induce autophagy, which can mitigate damage and stress. If this network is incapable of repairing the damage or overcoming continued stress, the default pathway of apoptosis is engaged to destroy the cell. Induction of macroautophagy by cancer therapeutics has led to clinical trials investigating combinations of HCQ (hydroxychloriquine) suppression of autophagy with apoptosis-inducing agents. Further study of the complex integration of autophagy, proteasomal degradation, UPR and apoptosis is likely to provide additional targets for our fight against cancer. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

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