2. Academic Validation
  3. ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5

ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5

  • Nat Chem Biol. 2019 Dec;15(12):1232-1240. doi: 10.1038/s41589-019-0399-y.
Yang Cao # 1,  Tian Qiu # 1,  Rahul S Kathayat # 1,  Saara-Anne Azizi 1 2,  Anneke K Thorne 1,  Daniel Ahn 1,  Yuko Fukata 3,  Masaki Fukata 3,  Phoebe A Rice 4,  Bryan C Dickinson 5
Affiliations

Affiliations

  • 1 Department of Chemistry, The University of Chicago, Chicago, IL, USA.
  • 2 Medical Scientist Training Program, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
  • 3 Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
  • 4 Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
  • 5 Department of Chemistry, The University of Chicago, Chicago, IL, USA. Dickinson@uchicago.edu.
  • # Contributed equally.
PMID: 31740833 DOI: 10.1038/s41589-019-0399-y
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.

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