Stress-Induced Transient Cell Cycle Arrest Coordinates Metabolic Resource Allocation to Balance Adaptive Tradeoffs

Abstract

The ability of a cell to mount a robust response to an environmental perturbation is paramount to its survival. While cells deploy a spectrum of specialized counter-measures to deal with stress, a near constant feature of these responses is a down regulation or arrest of the cell cycle. It has been widely assumed that this modulation of the cell cycle is instrumental in facilitating a timely response towards cellular adaptation. Here, we investigate the role of cell cycle arrest in the hyperosmotic shock response of the model organism S. cerevisiae by deleting the osmoshock-stabilized cell cycle inhibitor Sic1, thus enabling concurrent stress response activation and cell cycle progression. Contrary to expectation, we found that removal of stress-induced cell cycle arrest accelerated the adaptive response to osmotic shock instead of delaying it. Using a combination of time-lapse microscopy, genetic perturbations and quantitative mass spectrometry, we discovered that unabated cell cycle progression during stress enables the liquidation of internal glycogen stores, which are then shunted into the osmotic shock response to fuel a faster adaptation. Therefore, osmo-adaptation in wild type cells is delayed because cell cycle arrest diminishes the ability of the cell to tap its glycogen stores. However, acceleration of osmo-adaptation in mutant cells that do not arrest comes at the cost of acute sensitivity to a subsequent osmo-stress. This indicates that despite the ostensible advantage faster adaptation poses, there is a trade-off between the short-term benefit of faster adaptation and the vulnerability it poses to subsequent insults. We suggest that cell cycle arrest acts as a carbon flux valve to regulate the amount of material that is devoted to osmotic shock, balancing short term adaptation with long-term robustness.

The regulatory mechanism of the yeast osmoresponse under different glucose concentrations

“…A previous study reported that under rich-glucose conditions, yeast stored excess carbon in several metabolic pathways, and the first step of the osmotic stress response was to route internal stores of the metabolic flux to glycerol production, accelerating osmoadaptation. 32 However, our results show that metabolic flux redistribution may be more important (data not shown). When glucose was relatively abundant, the growth rate of the cells treated with 0.1% glucose was almost the same as that of the cells treated with 2% glucose.…”

IGFBP-3 Mediates Metabolic Homeostasis During Hyperosmolar Stress in the Corneal Epithelium

“…It is well established that metabolic changes and cell cycle control are bi-directional and osmotic stress has been shown to induce a transient cell cycle arrest in certain organisms. 56 This transient arrest is a counter-measure that mediates short term adaptation in response to stress and allows for a redistribution of the resources needed for survival. In contrast to this, the accumulation of cells at G0/G1 after 24 hours of hyperosmolar culture is most likely due to the higher energy demand required for cells to move into S phase.…”

Investigating molecular crowding during cell division and hyperosmotic stress in budding yeast with FRET

“…All these processes rely on biomolecular rearrangement and volume changes, and as such may impact local macromolecular crowding conditions. Cell growth is often inhibited during stress ( X. Li & Cai, 1999 ; Taïeb et al, 2021 ), correlated to diversion of metabolic resources diverted to mitigate the resultant detrimental physiological effects ( Bonny et al, 2020 ; Chasman et al, 2014 ). Growth capability is therefore a key parameter in measuring cellular recovery, with those that fail to reverse the arrest and re-enter a replicative cycle generally dying ( Petranovic & Ganley, 2014 ).…”