title: The conserved apicomplexan Aurora kinase TgArk3 is involved in endodyogeny, duplication rate and parasite virulence.
abstract: Aurora kinases are eukaryotic serine/threonine protein kinases that regulate key events associated with chromatin condensation, centrosome and spindle function and cytokinesis. Elucidating the roles of Aurora kinases in apicomplexan parasites is crucial to understand the cell cycle control during Plasmodium schizogony or Toxoplasma endodyogeny. Here, we report on the localization of two previously uncharacterized Toxoplasma Aurora-related kinases (Ark2 and Ark3) in tachyzoites and of the uncharacterized Ark3 orthologue in Plasmodium falciparum erythrocytic stages. In Toxoplasma gondii, we show that TgArk2 and TgArk3 concentrate at specific sub-cellular structures linked to parasite division: the mitotic spindle and intranuclear mitotic structures (TgArk2), and the outer core of the centrosome and the budding daughter cells cytoskeleton (TgArk3). By tagging the endogenous PfArk3 gene with the green fluorescent protein in live parasites, we show that PfArk3 protein expression peaks late in schizogony and localizes at the periphery of budding schizonts. Disruption of the TgArk2 gene reveals no essential function for tachyzoite propagation in vitro, which is surprising giving that the P. falciparum and P. berghei orthologues are essential for erythrocyte schizogony. In contrast, knock-down of TgArk3 protein results in pronounced defects in parasite division and a major growth deficiency. TgArk3-depleted parasites display several defects, such as reduced parasite growth rate, delayed egress and parasite duplication, defect in rosette formation, reduced parasite size and invasion efficiency and lack of virulence in mice. Our study provides new insights into cell cycle control in Toxoplasma and malaria parasites and highlights Aurora kinase 3 as potential drug target.
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, UMR5235 CNRS, Université Montpellier, Montpellier, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Berry
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: Chun-Ti
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, INSERM U1016, Institut Cochin, Paris, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Reininger
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Victoria, Australia, 3800.
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Carvalho
authors.affiliation: Department of Internal Medicine and Experimental Pathology, Immunology and Microbiology, American University of Beirut, Beirut 1107 2020, Lebanon.
authors.forename: Hiba
authors.initials: H
authors.lastname: El Hajj
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, UMR5235 CNRS, Université Montpellier, Montpellier, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Morlon-Guyot
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, UMR5235 CNRS, Université Montpellier, Montpellier, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Bordat
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, UMR5235 CNRS, Université Montpellier, Montpellier, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Lebrun
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: Marc-Jan
authors.initials: MJ
authors.lastname: Gubbels
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Victoria, Australia, 3800.
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, UMR5235 CNRS, Université Montpellier, Montpellier, France.
authors.forename: Wassim
authors.initials: W
authors.lastname: Daher
mesh_terms: D000818:Animals; D064127:Aurora Kinases / Q000502:physiology*; D005260:Female; D006790:Host-Parasite Interactions; D051379:Mice; D021381:Protein Transport; D015800:Protozoan Proteins / Q000502:physiology*; D014122:Toxoplasma / Q000201:enzymology* / Q000502:physiology / Q000648:ultrastructure; D014123:Toxoplasmosis / Q000469:parasitology*; D014774:Virulence
chemical_list: D015800:Protozoan Proteins; D064127:Aurora Kinases
keywords: Aurora kinases; Plasmodium falciparum; Toxoplasma gondii; apicomplexa; centrosome; endodyogeny; replication; schizogony; spindle pole bodies; tet-inducible system
references.citation: Open Biol. 2013 Mar 20;3(3):120185
references.pmid: 23516109
references.citation: Cell Microbiol. 2015 Apr;17(4):559-78
references.pmid: 25329540
references.citation: Science. 1987 Jun 26;236(4809):1661-6
references.pmid: 3299700
references.citation: Eukaryot Cell. 2009 Apr;8(4):530-9
references.pmid: 19218426
references.citation: Cell Microbiol. 2014 Jan;16(1):78-94
references.pmid: 24015880
references.citation: Int J Parasitol. 2011 Jan;41(1):71-80
references.pmid: 20816844
references.citation: Mol Biochem Parasitol. 1991 Apr;45(2):249-59
references.pmid: 2038358
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11703-7
references.pmid: 8265612
references.citation: J Cell Sci. 2002 Mar 1;115(Pt 5):1017-25
references.pmid: 11870220
references.citation: PLoS Pathog. 2010 Oct 07;6(10):e1001132
references.pmid: 20949068
references.citation: Science. 1993 Nov 5;262(5135):911-4
references.pmid: 8235614
references.citation: Mol Microbiol. 2011 Jan;79(1):205-21
references.pmid: 21166904
references.citation: J Cell Biol. 2000 Dec 25;151(7):1423-34
references.pmid: 11134072
references.citation: Nat Rev Mol Cell Biol. 2001 Jan;2(1):21-32
references.pmid: 11413462
references.citation: J Biol Chem. 1996 Jun 14;271(24):14010-9
references.pmid: 8662859
references.citation: Curr Opin Cell Biol. 2003 Dec;15(6):672-83
references.pmid: 14644191
references.citation: PLoS Biol. 2015 Mar 03;13(3):e1002093
references.pmid: 25734885
references.citation: Nucleic Acids Res. 2001 Nov 15;29(22):E115
references.pmid: 11713335
references.citation: Eukaryot Cell. 2012 Mar;11(3):343-52
references.pmid: 22210829
references.citation: J Cell Sci. 2013 Aug 1;126(Pt 15):3344-55
references.pmid: 23729737
references.citation: J Protozool. 1979 Aug;26(3):367-76
references.pmid: 536929
references.citation: Nat Commun. 2011 Nov 29;2:565
references.pmid: 22127061
references.citation: Nat Rev Mol Cell Biol. 2003 Nov;4(11):842-54
references.pmid: 14625535
references.citation: Mol Biochem Parasitol. 2001 Jul;115(2):165-75
references.pmid: 11420103
references.citation: J Ultrastruct Res. 1973 Feb;42(3):354-76
references.pmid: 4702924
references.citation: Nat Rev Microbiol. 2014 Feb;12(2):125-36
references.pmid: 24384598
references.citation: Mol Biol Cell. 2015 Dec 15;26(25):4562-76
references.pmid: 26466679
references.citation: Eukaryot Cell. 2011 Apr;10(4):474-82
references.pmid: 21317311
references.citation: Cell Microbiol. 2005 Dec;7(12):1823-33
references.pmid: 16309467
references.citation: J Protozool. 1975 Feb;22(1):71-84
references.pmid: 1117438
references.citation: J Parasitol. 1979 Jun;65(3):418-20
references.pmid: 383936
references.citation: PLoS Biol. 2012;10(12):e1001444
references.pmid: 23239939
references.citation: Cell Microbiol. 2014 Jan;16(1):95-114
references.pmid: 24011186
references.citation: J Cell Sci. 2006 Jun 1;119(Pt 11):2236-45
references.pmid: 16684814
references.citation: Cell Microbiol. 2015 Aug;17(8):1157-78
references.pmid: 25640905
references.citation: Int Rev Cell Mol Biol. 2012;298:1-31
references.pmid: 22878103
references.citation: Cell Microbiol. 2015 Jan;17(1):62-78
references.pmid: 25088010
references.citation: PLoS Pathog. 2011 Dec;7(12):e1002392
references.pmid: 22144892
references.citation: Parasitology. 1993 Apr;106 ( Pt 3):223-32
references.pmid: 8488059
references.citation: PLoS Pathog. 2010 Sep 09;6(9):e1001094
references.pmid: 20844581
references.citation: Biochim Biophys Acta. 2013 Jul;1834(7):1336-45
references.pmid: 23462523
references.citation: Parasitology. 1988 Aug;97 ( Pt 1):1-10
references.pmid: 3174230
references.citation: Prog Cell Cycle Res. 2000;4:163-83
references.pmid: 10740824
references.citation: Cell Microbiol. 2011 Jan;13(1):18-31
references.pmid: 20698859
references.citation: J Biomed Biotechnol. 2011;2011:473983
references.pmid: 22190852