Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2

• Published in: Developmental cell 2023-03, Vol.58 (5), p.376-397.e4
• Main Authors: Wu, Yeping, Lim, Ye-Wheen, Stroud, David A., Martel, Nick, Hall, Thomas E., Lo, Harriet P., Ferguson, Charles, Ryan, Michael T., McMahon, Kerrie-Ann, Parton, Robert G.
• Format: Article
• Language: English
• Subjects: Animals; caveolae; Caveolae - metabolism; CAVIN1; cell death; ferroptosis; Lipid Peroxidation; NF-E2-Related Factor 2 - metabolism; NRF2; Oxidative Stress; RNA-Binding Proteins - metabolism; Zebrafish - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2023.02.004

Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole-cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to lipid-peroxidation-induced ferroptosis. Thus, caveolae, via lipid peroxidation and CAVIN1 release, maintain cellular susceptibility to oxidative-stress-induced cell death, demonstrating a crucial role for this organelle in cellular homeostasis and wound response. [Display omitted] •Released CAVIN1 inactivates NRF2 under oxidative stress•Membrane lipid peroxidation triggers CAVIN1 release under oxidative stress•Cavin1 mediates ROS accumulation and tissue regeneration in zebrafish•Cancer cells lacking CAVIN1 are resistant to ferroptosis Wu et al. define a conserved pathway involving cell surface pits called caveolae, NRF2, and lipid peroxidation in sensing and responding to oxidative stress. They show the crucial role of this pathway in maintaining homeostatic cellular balance by promoting the elimination of severely damaged or malignant cells.