Nandakumar Shyama, Grmai Lydia, Vasudevan Deepika
Department of Cell Biology, University of Pittsburgh School of Medicine, PA, USA.
Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
FEBS J. 2025 Jul 14. doi: 10.1111/febs.70166.
Across phyla, organisms have evolved signaling mechanisms to cope with cell-intrinsic and -extrinsic stressors. The integrated stress response (ISR) is a prime example of such a mechanism and has well-defined roles from yeast to humans in dealing with stress burdens imposed by nutrient deprivation, protein misfolding, infectious agents, and oxidative stress. As with many fundamental cellular processes, the complexity of ISR signaling increases with evolutionary complexity. While single-celled organisms have been reported to utilize ISR signaling in the context of stress, multicellular organisms also rely on ISR signaling components for a number of homeostatic functions. The role of ISR signaling in the absence of obvious stressors is less well-studied, though useful insights into this can be extrapolated from prior studies using loss-of-function mutants in model organisms. This review summarizes the known (and inferred) homeostatic roles for ISR signaling components and speculates on cellular functions and principles that might require stress-adaptive mechanisms such as ISR signaling to maintain homeostasis.
在不同的生物门类中，生物体已经进化出信号传导机制来应对细胞内在和外在的应激源。综合应激反应（ISR）就是这样一种机制的典型例子，从酵母到人类，它在应对营养剥夺、蛋白质错误折叠、病原体和氧化应激所带来的应激负担方面具有明确的作用。与许多基本的细胞过程一样，ISR信号传导的复杂性随着进化复杂性的增加而增加。虽然据报道单细胞生物在应激情况下会利用ISR信号传导，但多细胞生物也依赖ISR信号传导成分来实现多种稳态功能。尽管可以从之前在模式生物中使用功能丧失突变体的研究中推断出一些有用的见解，但ISR信号传导在没有明显应激源的情况下所起的作用仍研究较少。本综述总结了ISR信号传导成分已知的（以及推断的）稳态作用，并推测了可能需要诸如ISR信号传导这样的应激适应机制来维持稳态的细胞功能和原理。
