title: Comparative gene identification-58 (CGI-58) promotes autophagy as a putative lysophosphatidylglycerol acyltransferase.
abstract: CGI-58 is a lipid droplet-associated protein that, when mutated, causes Chanarin-Dorfman syndrome in humans, which is characterized by excessive storage of triglyceride in various tissues. However, the molecular mechanisms underlying the defect remain elusive. CGI-58 was previously reported to catalyze the resynthesis of phosphatidic acid as a lysophosphatidic acid acyltransferase. In addition to triglyceride, phosphatidic acid is also used a substrate for the synthesis of various mitochondrial phospholipids. In this report, we investigated the propensity of CGI-58 in the remodeling of various phospholipids. We found that the recombinant CGI-58 overexpressed in mammalian cells or purified from Sf9 insect cells catalyzed efficiently the reacylation of lysophosphatidylglycerol to phosphatidylglycerol (PG), which requires acyl-CoA as the acyl donor. In contrast, the recombinant CGI-58 was devoid of acyltransferase activity toward other lysophospholipids. Accordingly, overexpression and knockdown of CGI-58 adversely affected the endogenous PG level in C2C12 cells. PG is a substrate for the synthesis of cardiolipin, which is required for mitochondrial oxidative phosphorylation and mitophagy. Consequently, overexpression and knockdown of CGI-58 adversely affected autophagy and mitophagy in C2C12 cells. In support for a key role of CGI-58 in mitophagy, overexpression of CGI-58 significantly stimulated mitochondrial fission and translocation of PINK1 to mitochondria, key steps involved in mitophagy. Furthermore, overexpression of CGI-58 promoted mitophagic initiation through activation of 5'-AMP-activated protein kinase and inhibition of mTORC1 mammalian target of rapamycin complex 1 signaling, the positive and negative regulators of autophagy, respectively. Together, these findings identified novel molecular mechanisms by which CGI-58 regulates lipid homeostasis, because defective autophagy is implicated in dyslipidemia and fatty liver diseases.
authors.affiliation: the Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 From the Beijing Key Laboratory of Gene Resource and Molecular Development and College of Life Sciences, Beijing Normal University, Beijing 100875, China and.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: the Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: the Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Jia
authors.initials: J
authors.lastname: Nie
authors.affiliation: the Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Ruili
authors.initials: R
authors.lastname: Han
authors.affiliation: From the Beijing Key Laboratory of Gene Resource and Molecular Development and College of Life Sciences, Beijing Normal University, Beijing 100875, China and ygzhai@bnu.edu.cn.
authors.forename: Yonggong
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: the Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 yus11@psu.edu.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D066292:Lipid Droplets / Q000378:metabolism; D050356:Lipid Metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D018613:Microscopy, Confocal; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000378:metabolism; D034622:RNA Interference; D061987:Sf9 Cells; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D046912:Multiprotein Complexes; D010715:Phosphatidylglycerols; C026223:lysophosphatidylglycerol; D000217:Acyltransferases; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: Autophagy; Lipid Droplet; Lipid Metabolism; Mammalian Target of Rapamycin (mTOR); Mitochondria