Interplay between NRF2 post-translational modifications and protein-protein interactions: Perspectives from emerging
Adem Ozleyen1, Seda Savranoglu Kulabas2, Miroslav Novak3
1Health Institutes of Turkiye, Turkiye Biotechnology Institute, Ankara, 06270, Turkiye.
Archives of Biochemistry and Biophysics
|May 7, 2026
Summary
Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cellular stress responses. Its stability and activity are controlled by protein interactions and post-translational modifications, crucial for adapting to physiological and stress conditions.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Transcription Factor Regulation
Background:
- Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor controlling cellular adaptation to stress.
- Kelch-like ECH-associated protein 1 (KEAP1) typically targets NRF2 for degradation under basal conditions.
- Stressors disrupt the KEAP1-NRF2 interaction, allowing NRF2 accumulation and transcriptional activity.
Purpose of the Study:
- To review current structural and functional data on NRF2 regulation.
- To highlight the roles of post-translational modifications (PTMs) and protein-protein interactions (PPIs) in NRF2 signaling.
- To emphasize the interplay between PTMs and PPIs in NRF2 function.
Main Methods:
- Literature review of structural and functional evidence.
- Analysis of regulatory mechanisms including PTMs and PPIs.
- Focus on both well-characterized and understudied modifications of NRF2.
Main Results:
- NRF2 activity is modulated by a complex network of PPIs, including regulators like PIN1.
- PTMs such as phosphorylation, ubiquitination, SUMOylation, and O-GlcNAcylation significantly impact NRF2 stability and function.
- Dynamic interplay between PTMs and PPIs shapes NRF2 signaling pathways.
Conclusions:
- NRF2 regulation is a sophisticated process involving numerous PTMs and PPIs.
- Understanding these regulatory networks is crucial for comprehending cellular adaptation to stress.
- Further research into less-characterized PTMs and PPIs will elucidate NRF2's role in health and disease.
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