title: The Plasmodium palmitoyl-S-acyl-transferase DHHC2 is essential for ookinete morphogenesis and malaria transmission.
abstract: The post-translational addition of C-16 long chain fatty acids to protein cysteine residues is catalysed by palmitoyl-S-acyl-transferases (PAT) and affects the affinity of a modified protein for membranes and therefore its subcellular localisation. In apicomplexan parasites this reversible protein modification regulates numerous biological processes and specifically affects cell motility, and invasion of host cells by Plasmodium falciparum merozoites and Toxoplasma gondii tachyzoites. Using inhibitor studies we show here that palmitoylation is key to transformation of zygotes into ookinetes during initial mosquito infection with P. berghei. We identify DHHC2 as a unique PAT mediating ookinete formation and morphogenesis. Essential for life cycle progression in asexual blood stage parasites and thus refractory to gene deletion analyses, we used promoter swap (ps) methodology to maintain dhhc2 expression in asexual blood stages but down regulate expression in sexual stage parasites and during post-fertilization development of the zygote. The ps mutant showed normal gamete formation, fertilisation and DNA replication to tetraploid cells, but was characterised by a complete block in post-fertilisation development and ookinete formation. Our report highlights the crucial nature of the DHHC2 palmitoyl-S-acyltransferase for transmission of the malaria parasite to the mosquito vector through its essential role for ookinete morphogenesis.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Edifício Egas Moniz, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Santos
authors.affiliation: Parasitology, Department of Infectious Diseases, University of Heidelberg Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kehrer
authors.affiliation: Leiden Malaria Research Group, Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Blandine
authors.initials: B
authors.lastname: Franke-Fayard
authors.affiliation: Parasitology, Department of Infectious Diseases, University of Heidelberg Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Frischknecht
authors.affiliation: Leiden Malaria Research Group, Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Edifício Egas Moniz, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal.|Parasitology, Department of Infectious Diseases, University of Heidelberg Medical School, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Gunnar R
authors.initials: GR
authors.lastname: Mair
mesh_terms: D020413:3' Untranslated Regions; D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D009033:Culicidae / Q000469:parasitology; D005260:Female; D008018:Life Cycle Stages / Q000187:drug effects; D054878:Lipoylation / Q000187:drug effects; D008288:Malaria / Q000469:parasitology* / Q000635:transmission*; D008807:Mice, Inbred BALB C; D009024:Morphogenesis / Q000187:drug effects; D010168:Palmitates / Q000494:pharmacology; D010962:Plasmodium berghei / Q000201:enzymology* / Q000254:growth & development; D011401:Promoter Regions, Genetic; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014122:Toxoplasma / Q000201:enzymology / Q000254:growth & development; D015053:Zygote / Q000187:drug effects / Q000254:growth & development
chemical_list: D020413:3' Untranslated Regions; D010168:Palmitates; D015800:Protozoan Proteins; D012333:RNA, Messenger; C022776:2-bromopalmitate; D000217:Acyltransferases