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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All structural data have been deposited in the Protein Data Bank (PDB: 6NY9). Additional data supporting the findings of this manuscript are available from the corresponding author upon reasonable request.
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This work was supported by the University of Chicago, the National Institute of General Medical Sciences of the National Institutes of Health (R35 GM119840, to B.C.D.) and a ‘Catalyst Award’ (to B.C.D.) from the Chicago Biomedical Consortium, with support from the Searle Funds at The Chicago Community Trust. The crystallographic work is based on research conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team beamline, 24-ID-C, which is supported by a grant from the National Institute of General Medical Sciences (P41 GM103403) from the National Institutes of Health. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. We thank the staff of the Advanced Photon Source at Argonne National Laboratory for providing technical advice during data collection, L. Hu (University of Chicago) for providing advice on crystal growth, D. Koirala (University of Chicago) for assistance with X-ray diffraction data collection, Y. Shao (University of Chicago) for advice on structure refinement and S. Ahmadiantehrani (University of Chicago) for assistance proofing the manuscript.
B.C.D. and R.S.K. have a patent (US20180147250A1) on the DPPs.
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Cao, Y., Qiu, T., Kathayat, R.S. et al. ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5. Nat Chem Biol 15, 1232–1240 (2019). https://doi.org/10.1038/s41589-019-0399-y
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