Program in Chemical and Physical Biology, Vanderbilt University, Nashville, TN, USA.
Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN, USA.
Sci Adv. 2021 Feb 19;7(8). doi: 10.1126/sciadv.abe1122. Print 2021 Feb.
Exposure of cells to diverse types of stressful environments differentially regulates cell fate. Although many types of stresses causing this differential regulation are known, it is unknown how changes over time of the same stressor regulate cell fate. Changes in extracellular osmolarity are critically involved in physiological and pathophysiological processes in several tissues. We observe that human cells survive gradual but not acute hyperosmotic stress. We find that stress, caspase, and apoptosis signaling do not activate during gradual stress in contrast to acute treatments. Contrary to the current paradigm, we see a substantial accumulation of proline in cells treated with gradual but not acute stresses. We show that proline can protect cells from hyperosmotic stress similar to the osmoprotection in plants and bacteria. Our studies found a cell fate switch that enables cells to survive gradually changing stress environments by preventing caspase activation and protect cells through proline accumulation.
细胞暴露于不同类型的应激环境会导致细胞命运的差异调节。虽然已知许多类型的应激可以导致这种差异调节，但尚不清楚同一应激源随时间的变化如何调节细胞命运。细胞外渗透压的变化在多种组织的生理和病理生理过程中起着至关重要的作用。我们观察到，人类细胞可以在逐渐升高的渗透压环境中存活，但不能在急性高渗环境中存活。我们发现，与急性处理相比，在逐渐升高的渗透压环境中，应激、半胱天冬酶和细胞凋亡信号不会激活。与当前的范式相反，我们在逐渐升高渗透压处理的细胞中看到脯氨酸的大量积累，但在急性渗透压处理的细胞中没有看到脯氨酸的积累。我们表明脯氨酸可以像植物和细菌中的渗透保护一样保护细胞免受高渗应激。我们的研究发现了一种细胞命运转换，通过防止半胱天冬酶的激活，使细胞能够在逐渐变化的应激环境中存活，并通过脯氨酸的积累来保护细胞。
