Autophagy in parasitic protists: Unique features and drug targets

Brennand, Ana; Gualdrón‐López, Melisa; Coppens, Isabelle; Rigden, Daniel J.; Ginger, Michael L.; Michels, Paul A.M.

doi:10.1016/j.molbiopara.2011.02.003

Cited by 111 publications

(114 citation statements)

References 122 publications

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“…Autophagy pathways in intraerythrocytic P. falciparum are largely uncharacterized. Plasmodium encodes nine putative autophagy-related genes (ATG), representing less than 30% of the complement of ATG genes in other eukaryotes (14); interestingly, none of these genes appeared to be specifically induced during starvation (Dataset S3). Also, there does not appear to be a significant isoleucine store, because parasites preconditioned in subsistence levels of isoleucine (20 μM) survived starvation as well as those conditioned in high (200 μM) isoleucine and because parasites detect isoleucine withdrawal almost immediately, as evidenced by rapid phosphorylation of PfeIF2α.…”

Section: Discussionmentioning

confidence: 99%

“…However, components of this response that are found in other organisms appear to be missing in Plasmodium (3,14). Even the one component involved in the canonical starvation response that is conserved, the GCN2 ortholog PfeIK1, is seemingly dispensable, because its absence does not compromise the viability of parasites under isoleucine-limiting conditions, despite a well-documented ability to phosphorylate PfeIF2α during starvation.…”

Section: Discussionmentioning

confidence: 99%

“…These transcription factors control the response to amino acid deprivation by turning on pathways for amino acid biosynthesis, among others (12,13). Plasmodium does not have a TOR complex (14) and lacks the downstream transcription factors and biosynthetic pathways that mediate GCN2 action. An ortholog of eIF2α and three putative eIF2α kinases have been identified previously in the P. falciparum genome (15)(16)(17).…”

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Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

Babbitt

Altenhofen

Cobbold

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

153

242

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The human malaria parasite Plasmodium falciparum is auxotrophic for most amino acids. Its amino acid needs are met largely through the degradation of host erythrocyte hemoglobin; however the parasite must acquire isoleucine exogenously, because this amino acid is not present in adult human hemoglobin. We report that when isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate. Isoleucine-starved parasites remain viable for 72 h and resume rapid growth upon resupplementation. Protein degradation during starvation is important for maintenance of this hibernatory state. Microarray analysis of starved parasites revealed a 60% decrease in the rate of progression through the normal transcriptional program but no other apparent stress response. Plasmodium parasites do not possess a TOR nutrient-sensing pathway and have only a rudimentary amino acid starvation-sensing eukaryotic initiation factor 2α (eIF2α) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2α, but kinase-knockout clones still are able to hibernate and recover, indicating that this pathway does not directly promote survival during isoleucine starvation. We conclude that P. falciparum, in the absence of canonical eukaryotic nutrient stress-response pathways, can cope with an inconsistent bloodstream amino acid supply by hibernating and waiting for more nutrient to be provided.protease | artemesinin | autophagy

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

Babbitt

Altenhofen

Cobbold

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

153

242

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“…As ATG8 remains associated with the autophagosome, GFP-ATG8 is a common molecular marker for tracking autophagosomes by fluorescence microscopy, from their formation to their delivery to the lysosome. Genes encoding proteins with similarity to the core ATG proteins in yeast and mammals have been described in Leishmania species, 19,20 suggesting that these parasites possess a functional autophagy pathway. Further characterization showed that Leishmania expressing GFP-ATG8 form GFP-labeled puncta corresponding to autophagosomes and that autophagy is induced by starvation, as in yeast and mammals, as well as increasing during differentiation.…”

Section: Introductionmentioning

confidence: 99%

Glycosome turnover inLeishmania majoris mediated by autophagy

et al. 2014

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Abbreviations: ATG, autophagy-related; GFP, green fluorescent protein; mC, mCherry fluorescent protein; MVT, multivesicular tubule; RFP, red fluorescent protein; TEM, transmission electron microscopy.Autophagy is a central process behind the cellular remodeling that occurs during differentiation of Leishmania, yet the cargo of the protozoan parasite's autophagosome is unknown. We have identified glycosomes, peroxisome-like organelles that uniquely compartmentalize glycolytic and other metabolic enzymes in Leishmania and other kinetoplastid parasitic protozoa, as autophagosome cargo. It has been proposed that the number of glycosomes and their content change during the Leishmania life cycle as a key adaptation to the different environments encountered. Quantification of RFP-SQL-labeled glycosomes showed that promastigotes of L. major possess »20 glycosomes per cell, whereas amastigotes contain »10. Glycosome numbers were significantly greater in promastigotes and amastigotes of autophagy-defective L. major Datg5 mutants, implicating autophagy in glycosome homeostasis and providing a partial explanation for the previously observed growth and virulence defects of these mutants. Use of GFP-ATG8 to label autophagosomes showed glycosomes to be cargo in »15% of them; glycosome-containing autophagosomes were trafficked to the lysosome for degradation. The number of autophagosomes increased 10-fold during differentiation, yet the percentage of glycosome-containing autophagosomes remained constant. This indicates that increased turnover of glycosomes was due to an overall increase in autophagy, rather than an upregulation of autophagosomes containing this cargo. Mitophagy of the single mitochondrion was not observed in L. major during normal growth or differentiation; however, mitochondrial remnants resulting from stress-induced fragmentation colocalized with autophagosomes and lysosomes, indicating that autophagy is used to recycle these damaged organelles. These data show that autophagy in Leishmania has a central role not only in maintaining cellular homeostasis and recycling damaged organelles but crucially in the adaptation to environmental change through the turnover of glycosomes.

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“…8,9 A potential role of autophagy during the differentiation of protozoan parasites is emerging. [10][11][12][13] A notable example has been illustrated for Trypanosoma brucei differentiation, in which a rapid turnover of glycosomes is facilitated by selective autophagy. 14,15 The autophagic machinery is also activated during the differentiation of Leishmania major and Trypanosoma cruzi into infective metacyclic forms, and during the encystation of Entamoeba histolytica and Acanthamoeba.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the ATG8-conjugation system in 2Plasmodiumspecies with special focus on the liver stage

et al. 2013

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Keywords: malaria, Plasmodium liver forms, cellular differentiation, autophagy-related genes, ATG8, apicoplast Abbreviations: ACP, acyl carrier protein; ATG, autophagy-related (gene); ATG, autophagy-related (protein); GABARAP, GABA(A) receptor-associated protein; GFP, green fluorescent protein; IEM, immunoelectron microscopy; IFA, immunofluorescence assays; LC3, microtubule-associated protein 1 light chain 3; mCherry, mCherry red fluorescent protein; ORF, open reading frame; PbATG3, Plasmodium berghei ATG3; PbATG7, Plasmodium berghei ATG7; PbATG8, Plasmodium berghei ATG8; PGK, phosphoglycerate kinase; PDM, product of the differences from the mean; PE, phosphatidylethanolamine; PfATG8, Plasmodium falciparum ATG8; p.i., post-infection; prApe1, precursor form of aminopeptidase I; PtdIns3P, phosphatidylinositol 3-phosphate; PV, parasitophorous vacuolePlasmodium 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.

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Autophagy in parasitic protists: Unique features and drug targets

Cited by 111 publications

References 122 publications

Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

Glycosome turnover inLeishmania majoris mediated by autophagy

Characterization of the ATG8-conjugation system in 2Plasmodiumspecies with special focus on the liver stage

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