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PreprintCited by 50Endoplasmic Reticulum Stress and DiseaseRNA and protein synthesis mechanismsPI3K/AKT/mTOR signaling in cancer

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Temporal control of the integrated stress response by a stochastic molecular switch

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Klein, Philipp, Kallenberger, Stefan M., Roth, Hanna, Roth, Karsten, Ly-Hartig, Thi Bach Nga, Magg, Vera, Aleš, Janez, Talemi, Soheil Rastgou, Qiang, Yu, Wolf, Steffen, Oleksiuk, Olga, Kurilov, Roma, Di Ventura, Barbara, Bartenschlager, Ralf, Eils, Roland, Rohr, Karl, Hamprecht, Fred A., Höfer, Thomas, Fackler, Oliver T., Stoecklin, Georg, Ruggieri, Alessia·2022·Science Advances
DOI 10.1101/2022.01.01.474691PMC PMC8942376

Preprint — published as 10.1126/sciadv.abk2022 · Paper page

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Abstract

Stress granules (SGs) are formed in the cytosol as an acute response to environmental cues and activation of the integrated stress response (ISR), a central signaling pathway controlling protein synthesis. Using chronic virus infection as stress model, we previously uncovered a unique temporal control of the ISR resulting in recurrent phases of SG assembly and disassembly. Here, we elucidate the molecular network generating this fluctuating stress response, by integrating quantitative experiments with mathematical modeling, and find that the ISR operates as a stochastic switch. Key elements controlling this switch are the cooperative activation of the stress-sensing kinase PKR, the ultrasensitive response of SG formation to the phosphorylation of the translation initiation factor eIF2α, and negative feedback via GADD34, a stress-induced subunit of protein phosphatase 1. We identify GADD34 mRNA levels as the molecular memory of the ISR that plays a central role in cell adaptation to acute and chronic stress.

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Metadata

Authors
Klein, P., Kallenberger, S. M., Roth, H., Roth, K., Ly-Hartig, T. B. N., Magg, V., Aleš, J., Talemi, S. R., Qiang, Y., Wolf, S., Oleksiuk, O., Kurilov, R., Di Ventura, B., Bartenschlager, R., Eils, R., Rohr, K., Hamprecht, F. A., Höfer, T., Fackler, O. T., Stoecklin, G., & Ruggieri, A.
Affiliations
  • Heidelberg University (DE)
  • German Cancer Research Center (DE)
Corresponding author
Ruggieri, Alessia
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2022-01-02
Volume
8
Issue
12
Pages
eabk2022-eabk2022
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2022.01.01.474691
PMC
PMC8942376
OpenAlex
W4220884191
Cited by
50
References
1
Citations by year
2026: 8 · 2025: 18 · 2024: 16 · 2023: 7 · 2022: 1
FWCI
5.61
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (240245660, 278001972, 272983813)
  • Bundesministerium für Bildung und Forschung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
integrated stress response, stress granules, PKR kinase, eIF2α phosphorylation, GADD34, protein phosphatase 1, negative feedback, molecular memory, protein synthesis regulation

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