title: The multifunctional autophagy pathway in the human malaria parasite, Plasmodium falciparum.
abstract: Autophagy is a catabolic pathway typically induced by nutrient starvation to recycle amino acids, but can also function in removing damaged organelles. In addition, this pathway plays a key role in eukaryotic development. To date, not much is known about the role of autophagy in apicomplexan parasites and more specifically in the human malaria parasite Plasmodium falciparum. Comparative genomic analysis has uncovered some, but not all, orthologs of autophagy-related (ATG) genes in the malaria parasite genome. Here, using a genome-wide in silico analysis, we confirmed that ATG genes whose products are required for vesicle expansion and completion are present, while genes involved in induction of autophagy and cargo packaging are mostly absent. We subsequently focused on the molecular and cellular function of P. falciparum ATG8 (PfATG8), an autophagosome membrane marker and key component of the autophagy pathway, throughout the parasite asexual and sexual erythrocytic stages. In this context, we showed that PfATG8 has a distinct and atypical role in parasite development. PfATG8 localized in the apicoplast and in vesicles throughout the cytosol during parasite development. Immunofluorescence assays of PfATG8 in apicoplast-minus parasites suggest that PfATG8 is involved in apicoplast biogenesis. Furthermore, treatment of parasite cultures with bafilomycin A 1 and chloroquine, both lysosomotropic agents that inhibit autophagosome and lysosome fusion, resulted in dramatic morphological changes of the apicoplast, and parasite death. Furthermore, deep proteomic analysis of components associated with PfATG8 indicated that it may possibly be involved in ribophagy and piecemeal microautophagy of the nucleus. Collectively, our data revealed the importance and specificity of the autophagy pathway in the malaria parasite and offer potential novel therapeutic strategies.
authors.affiliation: Graduate Program in Cell, Molecular, and Developmental Biology; University of California, Riverside; Riverside, CA USA; Department of Cell Biology and Neuroscience; University of California, Riverside; Riverside, CA USA.
authors.forename: Serena
authors.initials: S
authors.lastname: Cervantes
authors.affiliation: Department of Cell Biology and Neuroscience; University of California, Riverside; Riverside, CA USA.
authors.forename: Evelien M
authors.initials: EM
authors.lastname: Bunnik
authors.affiliation: Stowers Institute for Medical Research; Kansas City, MO USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Saraf
authors.affiliation: Department of Cell Biology and Neuroscience; University of California, Riverside; Riverside, CA USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Conner
authors.affiliation: Department of Cell Biology and Neuroscience; University of California, Riverside; Riverside, CA USA.
authors.forename: Aster
authors.initials: A
authors.lastname: Escalante
authors.affiliation: Stowers Institute for Medical Research; Kansas City, MO USA.
authors.forename: Mihaela E
authors.initials: ME
authors.lastname: Sardiu
authors.affiliation: Department of Cell Biology and Neuroscience; University of California, Riverside; Riverside, CA USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ponts
authors.affiliation: Department of Cell Biology and Neuroscience; University of California, Riverside; Riverside, CA USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Prudhomme
authors.affiliation: Stowers Institute for Medical Research; Kansas City, MO USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: Department of Cell Biology and Neuroscience; University of California, Riverside; Riverside, CA USA.
authors.forename: Karine G
authors.initials: KG
authors.lastname: Le Roch
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D063546:Apicoplasts / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005455:Fluorescent Antibody Technique; D005718:Gametogenesis / Q000187:drug effects; D017125:Genes, Protozoan; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects / Q000235:genetics; D010271:Parasites / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D010963:Plasmodium falciparum / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D021381:Protein Transport / Q000187:drug effects; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D049452:Green Fluorescent Proteins
keywords: Plasmodium; apicoplast biogenesis; autophagy; gametocytogenesis; protein traffic