title: Plasmodium falciparum ATG8 implicated in both autophagy and apicoplast formation.
abstract: Amino acid utilization is important for the growth of the erythrocytic stages of the human malaria parasite Plasmodium falciparum, however the molecular mechanism that permits survival of the parasite during conditions of limiting amino acid supply is poorly understood. We provide data here suggesting that an autophagy pathway functions in P. falciparum despite the absence of a typical lysosome for digestion of the autophagosomes. It involves PfATG8, which has a C-terminal glycine which is absolutely required for association of the protein with autophagosomes. Amino acid starvation provoked increased colocalization between PfATG8- and PfRAB7-labeled vesicles and acidification of the colabeled structures consistent with PfRAB7-mediated maturation of PfATG8-positive autophagosomes; this is a rapid process facilitating parasite survival. Immuno-electron microscopic analyses detected PfRAB7 and PfATG8 on double-membrane-bound vesicles and also near or within the parasite's food vacuole, consistent with autophagosomes fusing with the endosomal system before being routed to the food vacuole for digestion. In nonstarved parasites, PfATG8, but not PfRAB7, was found on the intact apicoplast membrane and on apicoplast-targeted vesicles and apicoplast remnants when the formation of the organelle was disrupted; a localization also requiring the C-terminal glycine. These findings suggest that in addition to a classical role in autophagy, which involves the PfRAB7-endosomal system and food vacuole, PfATG8 is associated with apicoplast-targeted vesicles and the mature apicoplast, and as such contributes to apicoplast formation and maintenance. Thus, PfATG8 may be unique in having such a second role in addition to the formation of autophagosomes required for classical autophagy.
authors.affiliation: Institute of Infection, Immunity and Inflammation; College of Medical, Veterinary and Life Sciences; University of Glasgow; Glasgow, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tomlins
authors.affiliation: INSERM U1016 CNRS UMR 8104; Institut Cochin; Université Paris Descartes; Sorbonne Paris Cité; Paris, France.
authors.forename: Fathia
authors.initials: F
authors.lastname: Ben-Rached
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; Glasgow, UK.
authors.forename: Roderick Am
authors.initials: RA
authors.lastname: Williams
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology; Institute of Infection, Immunity and Inflammation; College of Medical, Veterinary and Life Sciences; University of Glasgow; Glasgow, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Proto
authors.affiliation: Department of Molecular Microbiology and Immunology; Johns Hopkins University Bloomberg School of Public Health; Baltimore, MD USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.affiliation: Department of Molecular Parasitology; Bernhard Nocht Institute for Tropical Medicine; Hamburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Ruch
authors.affiliation: Department of Molecular Parasitology; Bernhard Nocht Institute for Tropical Medicine; Hamburg, Germany; M.G. DeGroote Institute for Infectious Disease Research and Department of Pathology and Molecular Medicine; McMaster University; Hamilton, Canada.
authors.forename: Tim W
authors.initials: TW
authors.lastname: Gilberger
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; Glasgow, UK.
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology; Institute of Infection, Immunity and Inflammation; College of Medical, Veterinary and Life Sciences; University of Glasgow; Glasgow, UK.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.affiliation: Institute of Infection, Immunity and Inflammation; College of Medical, Veterinary and Life Sciences; University of Glasgow; Glasgow, UK.
authors.forename: Sylke
authors.initials: S
authors.lastname: Müller
authors.affiliation: INSERM U1016 CNRS UMR 8104; Institut Cochin; Université Paris Descartes; Sorbonne Paris Cité; Paris, France.
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
mesh_terms: D000818:Animals; D063546:Apicoplasts / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071190:Autophagy-Related Protein 8 Family; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000166:cytology / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D015800:Protozoan Proteins / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism
chemical_list: C000593619:ATG8 protein, Plasmodium falciparum; D000071190:Autophagy-Related Protein 8 Family; D008840:Microfilament Proteins; D015800:Protozoan Proteins
keywords: ATG8; Plasmodium; RAB7; apicoplast; autophagy; endosome; food vacuole; malaria