title: Characterization of the ATG8-conjugation system in 2 Plasmodium species with special focus on the liver stage: possible linkage between the apicoplastic and autophagic systems?
abstract: Plasmodium parasites successfully colonize different habitats within mammals and mosquitoes, and adaptation to various environments is accompanied by changes in their organelle composition and size. Previously, we observed that during hepatocyte infection, Plasmodium discards organelles involved in invasion and expands those implicated in biosynthetic pathways. We hypothesized that this process is regulated by autophagy. Plasmodium spp. possess a rudimentary set of known autophagy-related proteins that includes the ortholog of yeast Atg8. In this study, we analyzed the activity of the ATG8-conjugation pathway over the course of the lifecycle of Plasmodium falciparum and during the liver stage of Plasmodium berghei. We engineered a transgenic P. falciparum strain expressing mCherry-PfATG8. These transgenic parasites expressed mCherry-PfATG8 in human hepatocytes and erythrocytes, and in the midgut and salivary glands of Anopheles mosquitoes. In all observed stages, mCherry-PfATG8 was localized to tubular structures. Our EM and colocalization studies done in P. berghei showed the association of PbATG8 on the limiting membranes of the endosymbiont-derived plastid-like organelle known as the apicoplast. Interestingly, during parasite replication in hepatocytes, the association of PbATG8 with the apicoplast increases as this organelle expands in size. PbATG3, PbATG7 and PbATG8 are cotranscribed in all parasitic stages. Molecular analysis of PbATG8 and PbATG3 revealed a novel mechanism of interaction compared with that observed for other orthologs. This is further supported by the inability of Plasmodium ATG8 to functionally complement atg8Δ yeast or localize to autophagosomes in starved mammalian cells. Altogether, these data suggests a unique role for the ATG8-conjugation system in Plasmodium parasites.
authors.affiliation: Department of Molecular Microbiology and Immunology; Malaria Research Institute; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA; Department of Microbiology & Immunology; Division of Infectious Diseases, Medical Sciences; Columbia University Medical Center; New York, NY USA.
authors.forename: Bamini
authors.initials: B
authors.lastname: Jayabalasingham
authors.affiliation: Department of Molecular Microbiology and Immunology; Malaria Research Institute; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA.
authors.forename: Christiane
authors.initials: C
authors.lastname: Voss
authors.affiliation: Department of Molecular Microbiology and Immunology; Malaria Research Institute; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ehrenman
authors.affiliation: Department of Molecular Microbiology and Immunology; Malaria Research Institute; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA.
authors.forename: Julia D
authors.initials: JD
authors.lastname: Romano
authors.affiliation: Department of Molecular Microbiology and Immunology; Malaria Research Institute; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Smith
authors.affiliation: Department of Microbiology & Immunology; Division of Infectious Diseases, Medical Sciences; Columbia University Medical Center; New York, NY USA; Department of Medicine Division of Infectious Diseases, Medical Sciences; Columbia University Medical Center; New York, NY USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Department of Molecular Microbiology and Immunology; Malaria Research Institute; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA; Department of Biochemistry and Molecular Biology; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA.
authors.forename: Juergen
authors.initials: J
authors.lastname: Bosch
authors.affiliation: Department of Molecular Microbiology and Immunology; Malaria Research Institute; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D063546:Apicoplasts / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D000071190:Autophagy-Related Protein 8 Family; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000276:immunology; D010271:Parasites / Q000276:immunology* / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*; D012441:Saccharomyces cerevisiae / Q000276:immunology; D029701:Saccharomyces cerevisiae Proteins / Q000276:immunology
chemical_list: C113757:ATG8 protein, S cerevisiae; D000953:Antigens, Protozoan; D000071190:Autophagy-Related Protein 8 Family; D008869:Microtubule-Associated Proteins; D029701:Saccharomyces cerevisiae Proteins
keywords: ATG8; Plasmodiumliver forms; apicoplast; autophagy-related genes; cellular differentiation; malaria