Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress
Vera Magg,
Alessandro Manetto,
Katja Kopp,
Chia Ching Wu,
Mohsen Naghizadeh,
Doris Lindner,
Lucy Eke,
Julia Welsch,
Stefan M. Kallenberger,
Johanna Schott,
Volker Haucke,
Nicolas Locker,
Georg Stoecklin,
Alessia Ruggieri
Affiliations
Vera Magg
Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, 69120 Heidelberg, Germany
Alessandro Manetto
Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, 69120 Heidelberg, Germany
Katja Kopp
Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, 69120 Heidelberg, Germany
Chia Ching Wu
Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, 69120 Heidelberg, Germany
Mohsen Naghizadeh
Heidelberg University, Medical Faculty Mannheim, Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3) and Mannheim Cancer Center (MCC), 68167 Mannheim, Germany
Doris Lindner
Heidelberg University, Medical Faculty Mannheim, Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3) and Mannheim Cancer Center (MCC), 68167 Mannheim, Germany
Lucy Eke
Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, UK
Julia Welsch
Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, 69120 Heidelberg, Germany
Stefan M. Kallenberger
Digital Health Center, Berlin Institute of Health (BIH) and Charité, 10178 Berlin, Germany; Medical Oncology, National Center for Tumor Diseases, Heidelberg University, 69120 Heidelberg, Germany
Johanna Schott
Heidelberg University, Medical Faculty Mannheim, Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3) and Mannheim Cancer Center (MCC), 68167 Mannheim, Germany
Volker Haucke
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry, and Pharmacy, 14195 Berlin, Germany
Nicolas Locker
Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, UK; The Pirbright Institute, GU24 0NF Pirbright, UK
Georg Stoecklin
Heidelberg University, Medical Faculty Mannheim, Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3) and Mannheim Cancer Center (MCC), 68167 Mannheim, Germany; Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Corresponding author
Alessia Ruggieri
Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Disease Research, 69120 Heidelberg, Germany; Corresponding author
Summary: The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of growth arrest and DNA damage-inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We establish that the 3′ untranslated region of PPP1R15A mRNA contains an active AU-rich element (ARE) recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a component of the transient ISR memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.
