1. ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5
- Author
-
Daniel Ahn, Phoebe A. Rice, Anneke K. Thorne, Tian Qiu, Saara-Anne Azizi, Masaki Fukata, Yang Cao, Yuko Fukata, Rahul S. Kathayat, and Bryan C. Dickinson
- Subjects
Antioxidant ,medicine.medical_treatment ,Mitochondrion ,Article ,03 medical and health sciences ,Thioesterase ,medicine ,Homeostasis ,Humans ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,030302 biochemistry & molecular biology ,HEK 293 cells ,Esterases ,Active site ,PRDX5 ,Peroxiredoxins ,Cell Biology ,Mitochondria ,Cell biology ,HEK293 Cells ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Peroxiredoxin ,Oxidation-Reduction ,Function (biology) - Abstract
S-Palmitoylation is a reversible lipid post-translational modification that has been observed on mitochondrial proteins, but both the regulation and functional consequences of mitochondrial S-palmitoylation are poorly understood. Here, we show that perturbing the ‘erasers’ of S-palmitoylation, acyl protein thioesterases (APTs), with either pan-active inhibitors or a mitochondrial-targeted APT inhibitor, diminishes the antioxidant buffering capacity of mitochondria. Surprisingly, this effect was not mediated by the only known mitochondrial APT, but rather by a resident mitochondrial protein with no known endogenous function, ABHD10. We show that ABHD10 is a member of the APT family of regulatory proteins and identify peroxiredoxin-5 (PRDX5), a key antioxidant protein, as a target of ABHD10 S-depalmitoylase activity. We then find that ABHD10 regulates the S-palmitoylation status of the nucleophilic active site residue of PRDX5, providing a direct mechanistic connection between ABHD10-mediated S-depalmitoylation of PRDX5 and its antioxidant capacity. A mitochondrial-targeted acyl protein thioesterase inhibitor enables the identification of ABHD10 as a mitochondrial S-depalmitoylase that acts on the nucleophilic active site residue of peroxiredoxin-5 to modulate its antioxidant capacity.
- Published
- 2019