title: PTEX is an essential nexus for protein export in malaria parasites.
abstract: During the blood stages of malaria, several hundred parasite-encoded proteins are exported beyond the double-membrane barrier that separates the parasite from the host cell cytosol. These proteins have a variety of roles that are essential to virulence or parasite growth. There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins. One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX). Although PTEX has been linked to the export of one class of exported proteins, there has been no direct evidence for its role and scope in protein translocation. Here we show, through the generation of two parasite lines defective for essential PTEX components (HSP101 or PTEX150), and analysis of a line lacking the non-essential component TRX2 (ref. 12), greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. This includes proteins containing the PEXEL motif (RxLxE/Q/D) and PEXEL-negative exported proteins (PNEPs). Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in Plasmodium falciparum, was significantly reduced in PTEX knockdown parasites. PTEX function was also essential for blood-stage growth, because even a modest knockdown of PTEX components had a strong effect on the parasite's capacity to complete the erythrocytic cycle both in vitro and in vivo. Hence, as the only known nexus for protein export in Plasmodium parasites, and an essential enzymic machine, PTEX is a prime drug target.
authors.affiliation: 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia [3].
authors.forename: Brendan
authors.initials: B
authors.lastname: Elsworth
authors.affiliation: 1] Deakin University, Waurn Ponds, 3216, Australia [2].
authors.forename: Kathryn
authors.initials: K
authors.lastname: Matthews
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia.
authors.forename: Catherine Q
authors.initials: CQ
authors.lastname: Nie
authors.affiliation: Deakin University, Waurn Ponds, 3216, Australia.
authors.forename: Ming
authors.initials: M
authors.lastname: Kalanon
authors.affiliation: 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Charnaud
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanders
authors.affiliation: Deakin University, Waurn Ponds, 3216, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Chisholm
authors.affiliation: Deakin University, Waurn Ponds, 3216, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Counihan
authors.affiliation: National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani 12120, Thailand.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: The University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Paco
authors.initials: P
authors.lastname: Pino
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Chan
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia.
authors.forename: Mauro F
authors.initials: MF
authors.lastname: Azevedo
authors.affiliation: The University of Melbourne, Parkville, Victoria, 3010 Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rogerson
authors.affiliation: 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia [3] The University of Melbourne, Parkville, Victoria, 3010 Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.affiliation: 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia [3] The University of Melbourne, Parkville, Victoria, 3010 Australia [4].
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: 1] Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia [2] Monash University, Clayton, Victoria, 3800, Australia [3].
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.affiliation: 1] Deakin University, Waurn Ponds, 3216, Australia [2].
authors.forename: Tania F
authors.initials: TF
authors.lastname: de Koning-Ward
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008018:Life Cycle Stages / Q000502:physiology; D008288:Malaria / Q000469:parasitology*; D046912:Multiprotein Complexes / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism / Q000469:parasitology
chemical_list: D006360:Heat-Shock Proteins; D046912:Multiprotein Complexes; D015800:Protozoan Proteins