Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape

Taivan Batjargal; Francesca Zappa; Ryan J Grant; Robert A Piscopio; Alex Chialastri; Siddharth S Dey; Diego Acosta-Alvear; Maxwell Z Wilson

doi:10.1016/j.cels.2023.06.001

Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape

Cell Syst. 2023 Jul 19;14(7):551-562.e5. doi: 10.1016/j.cels.2023.06.001.

Authors

Taivan Batjargal¹, Francesca Zappa², Ryan J Grant², Robert A Piscopio², Alex Chialastri³, Siddharth S Dey⁴, Diego Acosta-Alvear⁵, Maxwell Z Wilson⁶

Affiliations

¹ Biomolecular Science and Engineering Program, University of California Santa Barbara, Santa Barbara, CA, USA.
² Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA.
³ Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA, USA.
⁴ Center for BioEngineering, University of California Santa Barbara, Santa Barbara, CA, USA; Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA; Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA, USA.
⁵ Biomolecular Science and Engineering Program, University of California Santa Barbara, Santa Barbara, CA, USA; Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA; Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA. Electronic address: daa@lifesci.ucsb.edu.
⁶ Center for BioEngineering, University of California Santa Barbara, Santa Barbara, CA, USA; Biomolecular Science and Engineering Program, University of California Santa Barbara, Santa Barbara, CA, USA; Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA; Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA. Electronic address: mzw@ucsb.edu.

PMID: 37473728
DOI: 10.1016/j.cels.2023.06.001

Abstract

The integrated stress response (ISR) is a conserved signaling network that detects aberrations and computes cellular responses. Dissecting these computations has been difficult because physical and chemical inducers of stress activate multiple parallel pathways. To overcome this challenge, we engineered a photo-switchable control over the ISR sensor kinase PKR (opto-PKR), enabling virtual, on-target activation. Using light to control opto-PKR dynamics, we traced information flow through the transcriptome and for key downstream ISR effectors. Our analyses revealed a biphasic, proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal outcomes. We then constructed an ordinary differential equation (ODE) model of the ISR, which demonstrated the dependence of future stress responses on past stress. Finally, we tested our model using high-throughput light-delivery to map the stress memory landscape. Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords: Cryptochrome 2; RNA-seq; cellular resilience; integrated stress response; optogenetics; stress memory landscape; systems biology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Optogenetics*
Signal Transduction* / genetics
Transcriptome