1 Inserm U1242, Chemistry, Oncogenesis, Stress & Signaling, University of Rennes 1, Rennes, France.
2 Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
SLAS Discov. 2017 Aug;22(7):787-800. doi: 10.1177/2472555217701685. Epub 2017 Apr 28.
The unfolded protein response (UPR) is an integrated, adaptive biochemical process that is inextricably linked with cell homeostasis and paramount to maintenance of normal physiological function. Prolonged accumulation of improperly folded proteins in the endoplasmic reticulum (ER) leads to stress. This is the driving stimulus behind the UPR. As such, prolonged ER stress can push the UPR past beneficial functions such as reduced protein production and increased folding and clearance to apoptotic signaling. The UPR is thus contributory to the commencement, maintenance, and exacerbation of a multitude of disease states, making it an attractive global target to tackle conditions sorely in need of novel therapeutic intervention. The accumulation of information of screening tools, readily available therapies, and potential pathways to drug development is the cornerstone of informed clinical research and clinical trial design. Here, we review the UPR's involvement in health and disease and, beyond providing an in-depth description of the molecules found to target the three UPR arms, we compile all the tools available to screen for and develop novel therapeutic agents that modulate the UPR with the scope of future disease intervention.
未折叠蛋白反应（UPR）是一种综合的、适应性的生化过程，与细胞内稳态密切相关，对维持正常生理功能至关重要。内质网（ER）中错误折叠蛋白的长期积累会导致应激。这是 UPR 的驱动刺激。因此，长期的 ER 应激会促使 UPR 超越有益的功能，如减少蛋白质产生、增加折叠和清除，进而导致凋亡信号。因此，UPR 有助于多种疾病状态的开始、维持和恶化，使其成为一个有吸引力的全球靶点，以解决急需新型治疗干预的疾病。筛选工具、现有治疗方法和潜在药物开发途径的信息积累是有针对性临床研究和临床试验设计的基石。在这里，我们综述了 UPR 在健康和疾病中的作用，除了深入描述已发现靶向 UPR 三个分支的分子外，我们还汇集了所有可用于筛选和开发新型治疗剂的工具，以调节 UPR，为未来的疾病干预提供帮助。
