Temporal control of the integrated stress response by a stochastic molecular switch
Open accessPublished version of a preprint
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 messenger RNA 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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Cites
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Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 1× · see citing works
“…by additional aspects, including (i) the inherent stochasticity in GADD34 and PKR expression whose initial protein abundance is low ( 17 , 38 , 39 ); (ii) the inherent stochasticity of the infection process, as the number of particles entering a cell depends on a probabilistic process ( 40 );…”
Stochastic mRNA Synthesis in Mammalian Cells
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- 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)
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Corresponding author
- Ruggieri, Alessia
- ORCID
- Venue
- Science Advances
- Published
- 2022-03-25
- Volume
- 8
- Issue
- 12
- Pages
- eabk2022-eabk2022
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC8942376
- OpenAlex
- W4220884191
- Cited by
- 50
- References
- 6
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 16 · 2023: 7 · 2022: 1
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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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