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

Author:

Klein Philipp1ORCID,Kallenberger Stefan M.234ORCID,Roth Hanna1ORCID,Roth Karsten1,Ly-Hartig Thi Bach Nga56,Magg Vera1,Aleš Janez7ORCID,Talemi Soheil Rastgou8ORCID,Qiang Yu9ORCID,Wolf Steffen7ORCID,Oleksiuk Olga1,Kurilov Roma2,Di Ventura Barbara2ORCID,Bartenschlager Ralf110ORCID,Eils Roland23ORCID,Rohr Karl9,Hamprecht Fred A.7,Höfer Thomas8ORCID,Fackler Oliver T.11ORCID,Stoecklin Georg56ORCID,Ruggieri Alessia1ORCID

Affiliation:

1. Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Diseases Research, Heidelberg University, Heidelberg, Germany.

2. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

3. Digital Health Center, Berlin Institute of Health (BIH) and Charité, Berlin, Germany.

4. Medical Oncology, National Center for Tumor Diseases, Heidelberg University, Heidelberg, Germany.

5. Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

6. Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany.

7. HCI/IWR, Heidelberg University, Heidelberg, Germany.

8. Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

9. Biomedical Computer Vision Group, BioQuant, IPMB, Heidelberg University, Heidelberg, Germany.

10. Division Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.

11. Department of Infectious Diseases, Integrative Virology, Center for Integrative Infectious Diseases Research, Heidelberg University, Heidelberg, Germany.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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