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Updated: Jul 24, 2025

Measurements of Physiological Stress Responses in C. Elegans
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The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2

Julia Katharina Charlotte Kreß1, Christina Jessen1, Anita Hufnagel1

  • 1Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany.

Cell Reports
|July 6, 2023
PubMed

Insights

The integrated stress response (ISR) activates the NRF2 pathway via ATF4, enhancing cellular resilience. This NRF2 activation supports cancer cells by increasing cystine uptake and balancing glutathione levels.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The redox regulator NRF2 is activated by stress, controlling redox balance, metabolism, and immune responses.
  • The integrated stress response (ISR), mediated by ATF4, is crucial for tissue homeostasis and cancer plasticity.

Purpose of the Study:

  • To elucidate the link between the ISR and NRF2.
  • To investigate the role of ATF4 in NRF2 activation and cellular resilience.

Main Methods:

  • Analysis of NRF2 and ATF4 interactions.
  • Gene expression analysis focusing on CHAC1 and xCT.
  • Metabolic assays assessing glutathione and cystine levels.

Main Results:

  • ATF4 directly increases NRF2 transcription and induces CHAC1, essential for sustained NRF2 activation.
  • NRF2 upregulates cystine uptake via xCT, supporting ATF4-driven cells.
  • NRF2 also enhances thioredoxin systems, counterbalancing glutathione depletion.

Conclusions:

  • The NRF2 response acts as a secondary layer to the ISR, mediated by ATF4.
  • This interplay is critical for cellular resilience in various physiological and pathological conditions, including cancer.
Keywords:
ATF4CHAC1CP: Cell biologyGSHNRF2SLC7A11integrated stress responsemelanoma

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