The environmental stress response regulates biophysics of the cytoplasm and survival in quiescence

All organisms employ strategies to cope with changing environmental conditions. In budding yeast, nutrient deprivation induces a reversible non-proliferative state known as quiescence, characterized by extensive remodeling of gene expression, metabolism, and cellular biophysical properties. Yeast cells survive prolonged periods of starvation-induced quiescence, provided they can respire in the early stages of glucose withdrawal, and blocking respiration causes premature aging and markedly reduced survival and cytoplasmic diffusion. We find that respiration is required to initiate a quiescence-specific adaptive program. Induction of such a program prior to glucose withdrawal bypasses the need for respiration, rescuing survival and biophysical properties to the levels of respiration-competent cells. This rescue relies on proteomic adaptation and is mediated by Ras/PKA inactivation and Msn2/4-dependent activation of the environmental stress response, leading to modulation of cytoplasmic diffusion. Together, this enables long-term survival in quiescence even in the absence of respiration, underscoring the role of the stress response and the modulation of cytoplasmic properties in quiescence and aging.