How Our Bodies Remember Stress

The current study, reported in Cell Systems, uses a unique method to try and untangle the ISR’s response. The ISR uses four specific stress-responsive kinases, enzymes acting upon other signaling proteins, to down and up-regulate a host of proteins involved in our stress response. The unique methodology was to make one of those kinases, PKR, involved in our innate immune response to viral infections, to be switched on by light that was otherwise harmless to the cells – they created an optogenetic switch that allowed them to control the “dose” and timing of stress and tease out ISR’s underlying patterns of transcriptional change.

The integrated stress response has an acute, transitory phase and a more gradual chronic mode.

• In the acute phase, ISR is associated with adaptive remodeling of the proteome and altering cell identity – trying to cope with the stress and return to a more homeostatic condition. Meanwhile, in the background, and developing far more gradually, other up-regulated genes prepare for cell death – preparing “the cell for inducing programmed death should the adaptative response turn out to be insufficient to deal with the stress.”
• The adaptive phase peaks at around 4 hours and the gradual phase at 10 hours creating a temporal pattern. The intensity of the stress (the dose) increased the degree of response, but the response was, as with most biological systems, non-linear. The timing of the two phases was unchanged by the stress intensity.

Using the data as a guide, the researchers constructed a model incorporating the temporal and qualitative changes in ISR’s alteration of transcription. In altering the duration of stress and the recovery periods, the researchers found a lag between the onset of a stressor and the cellular response – a feature termed hysteresis. More importantly, as the frequency of stress increased and the recovery phase shortened, the transcriptional pattern changed – the cellular acute response became more muted, making the chronic transcriptional changes more pronounced. As they write,

“In healthy cells challenged with short durations of stress, the ISR induces an adaptive response that increases resilience. On the other hand, this same pathway, when chronically activated, causes disease marked by reduced cellular function and increased cell death.”

Kelly Clarkson was only partially correct, “What doesn't kill you makes you stronger,” but only in small doses. Chronic stress impacts the ISR quite differently from short-term stress. The attenuation of the ISR’s acute “repair” is a chemical “stress memory landscape.”

“Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters.”

Source: Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape Cell Systems DOI: 1016/j.cels.2023.06.001

Virtual stress plays tricks on cells Cell Systems DOI: 10.1016/j.cels.2023.06.006