The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2
Julia Katharina Charlotte Kreß,
Christina Jessen,
Anita Hufnagel,
Werner Schmitz,
Thamara Nishida Xavier da Silva,
Ancély Ferreira dos Santos,
Laura Mosteo,
Colin R. Goding,
José Pedro Friedmann Angeli,
Svenja Meierjohann
Affiliations
Julia Katharina Charlotte Kreß
Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany
Christina Jessen
Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany
Anita Hufnagel
Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany
Werner Schmitz
Department of Biochemistry and Molecular Biology, University of Würzburg, 97074 Würzburg, Germany
Thamara Nishida Xavier da Silva
Rudolf-Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, 97080 Würzburg, Germany
Ancély Ferreira dos Santos
Rudolf-Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, 97080 Würzburg, Germany
Laura Mosteo
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal
Colin R. Goding
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK
José Pedro Friedmann Angeli
Rudolf-Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, 97080 Würzburg, Germany
Svenja Meierjohann
Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080 Würzburg, Germany; Corresponding author
Summary: The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.
