RT Journal Article
SR Electronic
T1 Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.24.493309
DO 10.1101/2022.05.24.493309
A1 Taivan Batjargal
A1 Francesca Zappa
A1 Ryan J Grant
A1 Robert A Piscopio
A1 Alex Chialastri
A1 Siddharth S Dey
A1 Diego Acosta-Alvear
A1 Maxwell Z Wilson
YR 2022
UL http://biorxiv.org/content/early/2022/05/25/2022.05.24.493309.abstract
AB The Integrated Stress Response (ISR) is a conserved signaling network that detects cellular damage and computes adaptive or terminal outcomes. Understanding the mechanisms that underly these computations has been difficult because natural stress inputs activate multiple parallel signaling pathways and classical ISR inducers have pleiotropic effects. To overcome this challenge, we engineered photo-switchable control over the ISR stress sensor kinase PKR (opto-PKR), which allows virtual control of the ISR. Using controlled light inputs to activate opto-PKR we traced information flow in the ISR both globally, in the transcriptome, and for key ISR effectors. Our analyses revealed a biphasic, input-proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal ISR outcomes. Using this data, we constructed an ordinary differential equation (ODE) model of the ISR which predicted system hysteresis dependent on prior stress durations and that stress memory encoding may lead to resilience. Our results demonstrate that the input dynamics of the ISR encode information in stress levels, durations, and the timing between stress encounters.Competing Interest StatementThe authors have declared no competing interest.