Abstract 1506: Protein acyl-protein thioesterases affect redox homeostasis and ROS signaling through peroxiredoxin

• Published in: Cancer research (Chicago, Ill.) Vol. 85; no. 8_Supplement_1; p. 1506
• Main Authors: Qiu, Tian, Azizi, Saara-Anne, Pani, Shubhashree, Dickinson, Bryan C.
• Format: Journal Article
• Language: English
• Published: 21.04.2025
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2025-1506

Peroxiredoxins (PRDXs) are among the most abundant antioxidants and are widely distributed in cancers. They are associated with tumor cell resistance to cell death, such as apoptosis and ferroptosis. Post-translational modifications of PRDX play a critical role in modulating its activity and tuning the balance between reactive oxygen species (ROS) signaling and stress. We previously discovered that mitochondrial localized PRDX3 and PRDX5 are S-acylated, with dynamic PRDX5 active site cysteine acylation regulating mitochondrial redox homeostasis. In this investigation, we found that all the PRDX family proteins are subject to S-acylation at the nucleophilic cysteine residue in their active site, and that PRDX S-acylation responds dynamically to ROS levels in the cell. The PRDX S-acylation level decreases under acute ROS stress, and increases under physiological, signaling levels of H2O2. Using activity-based fluorescent imaging with DPP-Red, a red-shifted fluorescent indicator for acyl-protein thioesterase (APT) activity, we also discovered that ROS-stress via exogenous H2O2 activates both the cytosolic and mitochondrial APTs, whereas EGF-stimulated endogenous H2O2 deactivates the cytosolic APTs. These results indicate that APTs help tune H2O2 signal transduction and ROS protection through PRDX S-deacylation.