Proteostasis & Cancer Team INSERM U1242 « Chemistry, Oncogenesis Stress Signaling », Université de Rennes, CEDEX, 35042 Rennes, France.
Centre de Lutte contre le Cancer Eugène Marquis, CEDEX, 35042 Rennes, France.
Cells. 2019 Oct 29;8(11):1347. doi: 10.3390/cells8111347.
Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors involved in such process, both endoplasmic reticulum (ER) and the Golgi complex play prominent roles in protein synthesis, biogenesis and secretion. ER and Golgi functions ensure that only properly folded proteins are allowed to flow through the secretory pathway while improperly folded proteins have to be eliminated to not impinge on cellular functions. Thus, complex quality control and degradation machineries are crucial to prevent the toxic accumulation of improperly folded proteins. However, in some instances, improperly folded proteins can escape the quality control systems thereby contributing to several human diseases. Herein, we summarize how the early secretory pathways copes with the accumulation of improperly folded proteins, and how insufficient handling can cause the development of several human diseases. Finally, we detail the genetic and pharmacologic approaches that could be used as potential therapeutic tools to treat these diseases.
正确折叠的蛋白质和未达到这种状态的蛋白质之间的区分对于细胞实现功能是必要的。真核细胞已经进化出几种机制来确保分泌蛋白的质量控制，从而在蛋白质生产中实现效率和保真度。在涉及到这种过程的参与者中，内质网 (ER) 和高尔基体复合物在蛋白质合成、生物发生和分泌中发挥着突出的作用。ER 和高尔基体的功能确保只有正确折叠的蛋白质才能通过分泌途径，而未正确折叠的蛋白质必须被消除，以免影响细胞功能。因此，复杂的质量控制和降解机制对于防止未正确折叠的蛋白质的毒性积累至关重要。然而，在某些情况下，未正确折叠的蛋白质可以逃避质量控制系统，从而导致多种人类疾病的发生。在此，我们总结了早期分泌途径如何应对未正确折叠蛋白质的积累，以及处理不足如何导致多种人类疾病的发展。最后，我们详细介绍了可作为治疗这些疾病的潜在治疗工具的遗传和药理学方法。
