Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function
Karen Rosier,
Molly T. McDevitt,
Joél Smet,
Brendan J. Floyd,
Maxime Verschoore,
Maria J. Marcaida,
Craig A. Bingman,
Irma Lemmens,
Matteo Dal Peraro,
Jan Tavernier,
Benjamin F. Cravatt,
Natalia V. Gounko,
Katlijn Vints,
Yenthe Monnens,
Kritika Bhalla,
Laetitia Aerts,
Edrees H. Rashan,
Arnaud V. Vanlander,
Rudy Van Coster,
Luc Régal,
David J. Pagliarini,
John W.M. Creemers
Affiliations
Karen Rosier
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium
Molly T. McDevitt
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Joél Smet
Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
Brendan J. Floyd
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Maxime Verschoore
Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
Maria J. Marcaida
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Craig A. Bingman
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Irma Lemmens
Center for Medical Biotechnology, VIB, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
Matteo Dal Peraro
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Jan Tavernier
Center for Medical Biotechnology, VIB, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
Benjamin F. Cravatt
The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Natalia V. Gounko
VIB-KU Leuven Center for Brain & Disease Research, Electron Microscopy Platform & VIB-Bioimaging Core, Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
Katlijn Vints
VIB-KU Leuven Center for Brain & Disease Research, Electron Microscopy Platform & VIB-Bioimaging Core, Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
Yenthe Monnens
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium
Kritika Bhalla
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium
Laetitia Aerts
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium
Edrees H. Rashan
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Arnaud V. Vanlander
Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
Rudy Van Coster
Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
Luc Régal
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium; Department of Pediatrics, Pediatric Neurology and Metabolism, UZ Brussel, Brussels, Belgium
David J. Pagliarini
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53715, USA; Departments of Cell Biology and Physiology, Biochemistry and Molecular Biophysics, and Genetics, Washington University School of Medicine, St Louis, MO 63110, USA; Corresponding author
John W.M. Creemers
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium; Corresponding author
Summary: Deficiency of the serine hydrolase prolyl endopeptidase-like (PREPL) causes a recessive metabolic disorder characterized by neonatal hypotonia, feeding difficulties, and growth hormone deficiency. The pathophysiology of PREPL deficiency and the physiological substrates of PREPL remain largely unknown. In this study, we connect PREPL with mitochondrial gene expression and oxidative phosphorylation by analyzing its protein interactors. We demonstrate that the long PREPLL isoform localizes to mitochondria, whereas PREPLS remains cytosolic. Prepl KO mice showed reduced mitochondrial complex activities and disrupted mitochondrial gene expression. Furthermore, mitochondrial ultrastructure was abnormal in a PREPL-deficient patient and Prepl KO mice. In addition, we reveal that PREPL has (thio)esterase activity and inhibition of PREPL by Palmostatin M suggests a depalmitoylating function. We subsequently determined the crystal structure of PREPL, thereby providing insight into the mechanism of action. Taken together, PREPL is a (thio)esterase rather than a peptidase and PREPLL is involved in mitochondrial homeostasis.
