title: Phosphatidic Acid-Mediated Signaling Regulates Microneme Secretion in Toxoplasma.
abstract: The obligate intracellular lifestyle of apicomplexan parasites necessitates an invasive phase underpinned by timely and spatially controlled secretion of apical organelles termed micronemes. In Toxoplasma gondii, extracellular potassium levels and other stimuli trigger a signaling cascade culminating in phosphoinositide-phospholipase C (PLC) activation, which generates the second messengers diacylglycerol (DAG) and IP3 and ultimately results in microneme secretion. Here we show that a delicate balance between DAG and its downstream product, phosphatidic acid (PA), is essential for controlling microneme release. Governing this balance is the apicomplexan-specific DAG-kinase-1, which interconverts PA and DAG, and whose depletion impairs egress and causes parasite death. Additionally, we identify an acylated pleckstrin-homology (PH) domain-containing protein (APH) on the microneme surface that senses PA during microneme secretion and is necessary for microneme exocytosis. As APH is conserved in Apicomplexa, these findings highlight a potentially widely used mechanism in which key lipid mediators regulate microneme exocytosis.
authors.affiliation: Department of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Bullen
authors.affiliation: Department of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Yonggen
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Apicolipid group, Institut Albert Bonniot UMR5309, CNRS, Université Grenoble Alpes, INSERM, Domaine de la Merci, 38700, La Tronche, France.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaryo-Botté
authors.affiliation: Department of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Hugo
authors.initials: H
authors.lastname: Bisio
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, 1150 14 W. Medical Center Dr., Ann Arbor, MI 48109-5620, USA.
authors.forename: Ou
authors.initials: O
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Natacha Klages
authors.initials: NK
authors.lastname: Jemelin
authors.affiliation: Department of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Marq
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, 1150 14 W. Medical Center Dr., Ann Arbor, MI 48109-5620, USA.
authors.forename: Vern
authors.initials: V
authors.lastname: Carruthers
authors.affiliation: Apicolipid group, Institut Albert Bonniot UMR5309, CNRS, Université Grenoble Alpes, INSERM, Domaine de la Merci, 38700, La Tronche, France.
authors.forename: Cyrille Y
authors.initials: CY
authors.lastname: Botté
authors.affiliation: Department of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland. Electronic address: dominique.soldati-favre@unige.ch.
authors.forename: Dominique
authors.initials: D
authors.lastname: Soldati-Favre
mesh_terms: D019852:Diacylglycerol Kinase / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D015388:Organelles / Q000187:drug effects* / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014122:Toxoplasma / Q000502:physiology*
chemical_list: D004075:Diglycerides; D010712:Phosphatidic Acids; D015800:Protozoan Proteins; D019852:Diacylglycerol Kinase
keywords: Apicomplexa; Toxoplasma gondii; diacylglycerol kinase; invasion; microneme; phosphatidic acid; phosphatidic acid phosphatase; phosphoinositide-phospholipase C; pleckstrin homology domain; propranolol; regulated exocytosis