Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function

• DOI: 10.1016/j.isci.2021.103460
• Publication Date: 2021-11-14T03:42:23Z
• Authors: 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
• Keywords: Molecular biology; Science; prepl deficiency; PROTEIN; Article; COMPLEX-I; ACYLAMINOACYL PEPTIDASE; 03 medical and health sciences; acylaminoacyl peptidase; Medicine and Health Sciences; aeropyrum-pernix k1; CRYSTAL-STRUCTURE; deletion; cystinuria; AEROPYRUM-PERNIX K1; 0303 health sciences; Molecular medicine; DELETION; Q; Biology and Life Sciences; crystal-structure; CYSTINURIA; oligopeptidase; PREPL DEFICIENCY; complex-i; bone-mineral density; BONE-MINERAL DENSITY; protein; Structural biology; OLIGOPEPTIDASE

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.