title: A novel role for 12/15-lipoxygenase in regulating autophagy.
abstract: 12/15-Lipoxygenase (LOX) enzymatically generates oxidized phospholipids in monocytes and macrophages. Herein, we show that cells deficient in 12/15-LOX contain defective mitochondria and numerous cytoplasmic vacuoles containing electron dense material, indicating defects in autophagy or membrane processing, However, both LC3 expression and lipidation were normal both basally and on chloroquine treatment. A LOX-derived oxidized phospholipid, 12-hydroxyeicosatetraenoic acid-phosphatidylethanolamine (12-HETE-PE) was found to be a preferred substrate for yeast Atg8 lipidation, versus native PE, while both native and oxidized PE were effective substrates for LC3 lipidation. Last, phospholipidomics demonstrated altered levels of several phospholipid classes. Thus, we show that oxidized phospholipids generated by 12/15-LOX can act as substrates for key proteins required for effective autophagy and that cells deficient in this enzyme show evidence of autophagic dysfunction. The data functionally link phospholipid oxidation with autophagy for the first time.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Alwena H
authors.initials: AH
authors.lastname: Morgan
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Hammond
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Nagatsuta 4259-S2-12, Yokohama, Japan.
authors.forename: Machiko
authors.initials: M
authors.lastname: Sakoh-Nakatogawa
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Nagatsuta 4259-S2-12, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohsumi
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Thomas
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Fabien
authors.initials: F
authors.lastname: Blanchet
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Piguet
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Langley Hall, 4249 Fifth Avenue, Pittsburgh, PA 15260, USA.
authors.forename: Kirill
authors.initials: K
authors.lastname: Kiselyov
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: o-donnellvb@cardiff.ac.uk.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics*; D000071190:Autophagy-Related Protein 8 Family; D050356:Lipid Metabolism / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: C475064:12-15-lipoxygenase; C113757:ATG8 protein, S cerevisiae; D000071190:Autophagy-Related Protein 8 Family; D008869:Microtubule-Associated Proteins; D010743:Phospholipids; D029701:Saccharomyces cerevisiae Proteins; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: Autophagy; Lipid; Lipoxygenase; Mitochondria