Emerging roles for integrated stress response signaling in homeostasis

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.