Exploring the role of the AMBRA1 protein in the regulation of the NRF2-KEAP1 pathway

Cells are continuously exposed to reactive oxygen species (ROS) and other pro-oxidants from both external and internal sources. ROS play a dual role in cellular functions, being crucial for the control of various physiological processes but also causing oxidative stress, when their levels increase. Oxidative stress is a critical factor for the development of several major diseases, including neurodegenerative and neuropsychiatric disorders, diabetes, and cancer. To counteract oxidative stress, cells have evolved intricate antioxidant defense systems. A central figure in this defense is the nuclear factor erythroid 2-related factor 2 (NRF2), which controls a broad array of antioxidant and detoxification enzymes. Under normal conditions, NRF2 levels are kept low by the Kelch-like ECH- associated protein 1 (KEAP1), which targets NRF2 by ubiquitin-mediated degradation via the proteasome system. However, during oxidative stress, NRF2 is stabilized, allowing its translocation into the nucleus, where it binds to the antioxidant response element (ARE), thereby promoting the transcription of oxidative stress response genes. Another crucial player in cellular regulation is the Activating Molecule in Beclin-1-Regulated Autophagy 1 (AMBRA1), a key regulator of autophagy, coordinating the formation and maturation of autophagosomes essential for maintaining cellular homeostasis and survival during stress. Additionally, it modulates the cell cycle, by influencing cyclin-dependent kinases, and oxidative stress, by promoting mitophagy to clear damaged mitochondria and prevent ROS accumulation. Our data indicate that, under physiological conditions, AMBRA1 interacts with KEAP1 and regulates KEAP1 stability, thereby influencing NRF2 activity. Understanding how AMBRA1 regulates the oxidative stress response via the NRF2/KEAP1 pathway is essential to advance our understanding of the mechanisms of cellular protection from oxidative damage.