The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2
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) a...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2023
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| Subjects: |
| _version_ | 1826310946212020224 |
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| author | Kreß, JKC Jessen, C Hufnagel, A Schmitz, W Xavier da Silva, TN Ferreira dos Santos, A Mosteo, L Goding, CR Friedmann Angeli, JP Meierjohann, S |
| author_facet | Kreß, JKC Jessen, C Hufnagel, A Schmitz, W Xavier da Silva, TN Ferreira dos Santos, A Mosteo, L Goding, CR Friedmann Angeli, JP Meierjohann, S |
| author_sort | Kreß, JKC |
| collection | OXFORD |
| description | 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 <i>CHAC1</i>, 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. |
| first_indexed | 2024-03-07T08:01:05Z |
| format | Journal article |
| id | oxford-uuid:ce9a123e-fa2d-43a8-bf40-7780c4bc311c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:01:05Z |
| publishDate | 2023 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:ce9a123e-fa2d-43a8-bf40-7780c4bc311c2023-09-27T15:55:27ZThe integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ce9a123e-fa2d-43a8-bf40-7780c4bc311cCell biologyEnglishSymplectic ElementsCell Press2023Kreß, JKCJessen, CHufnagel, ASchmitz, WXavier da Silva, TNFerreira dos Santos, AMosteo, LGoding, CRFriedmann Angeli, JPMeierjohann, SThe 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 <i>CHAC1</i>, 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. |
| spellingShingle | Cell biology Kreß, JKC Jessen, C Hufnagel, A Schmitz, W Xavier da Silva, TN Ferreira dos Santos, A Mosteo, L Goding, CR Friedmann Angeli, JP Meierjohann, S The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 |
| title | The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 |
| title_full | The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 |
| title_fullStr | The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 |
| title_full_unstemmed | The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 |
| title_short | The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 |
| title_sort | integrated stress response effector atf4 is an obligatory metabolic activator of nrf2 |
| topic | Cell biology |
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