TY  - JOUR
A1  - Kreß, Julia Katharina Charlotte
A1  - Jessen, Christina
A1  - Hufnagel, Anita
A1  - Schmitz, Werner
A1  - Da Xavier Silva, Thamara Nishida
A1  - Ferreira Dos Santos, Ancély
A1  - Mosteo, Laura
A1  - Goding, Colin R.
A1  - Friedmann Angeli, José Pedro
A1  - Meierjohann, Svenja
T1  - The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2
T2  - Cell Reports
N2  - Highlights
• The integrated stress response leads to a general ATF4-dependent activation of NRF2
• ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization
• An elevation of NRF2 transcript levels fosters this effect
• NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply

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.
KW  - NRF2
KW  - ATF4
KW  - integrated stress response
KW  - CHAC1
KW  - melanoma
KW  - SLC7A11
KW  - GSH
Y1  - 2023
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/35031
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-350312
VL  - 42
IS  - 7
ER  -