Autophagy in Apicomplexa: a life sustaining death mechanism?

Sinai, Anthony P.; Roepe, Paul D.

doi:10.1016/j.pt.2012.06.006

Cited by 44 publications

(42 citation statements)

References 57 publications

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“…Of course, in these divergent eukaryotes, pleiotropic functions are possible for autophagy proteins and their involvement in cellular processes promoting either life or death is currently being investigated. 12,13 In the present report, we provide a further characterization of TgATG8 and its regulation machinery and reveal several unusual features for this protein and associated peptidase TgATG4.…”

Section: Introductionmentioning

confidence: 64%

“…This has led to the establishment of speculative models as to which roles autophagy might play in these parasites, which is complicated by the fact that they have complex life cycles, with several developmental forms where autophagy may have different functions. 12,13 Functional studies are thus needed to better characterize this machinery in the parasites and we have previously generated the first conditional mutant for a Toxoplasma ATG protein, TgATG3, which is involved in the conjugation of TgATG8. 11 The data we have obtained, expanded with the current study, show that TgATG3 and TgATG4 (whose functions are linked to TgATG8) and, apparently, TgATG8 itself, are important for parasite growth.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

et al. 2013

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in the process of autophagy, the Atg8 protein is conjugated, through a ubiquitin-like system, to the lipid phosphatidylethanolamine (Pe) to associate with the membrane of forming autophagosomes. There, it plays a crucial role in the genesis of these organelles and in autophagy in general. in most eukaryotes, the cysteine peptidase Atg4 processes the c terminus of cytosolic Atg8 to regulate its association with autophagosomal membranes and also delipidates Atg8 to release this protein from membranes. The parasitic protist Toxoplasma gondii contains a functional, yet apparently reduced, autophagic machinery. T. gondii Atg8 homolog, in addition to a cytosolic and occasionally autophagosomal localization, also localizes to the apicoplast, a nonphotosynthetic plastid bounded by four membranes. Our attempts to interfere with TgATG8 function showed that it appears to be essential for parasite multiplication inside its host cell. This protein also displays a peculiar c terminus that does not seem to necessitate processing prior to membrane association and yet an unusually large Toxoplasma homolog of ATG4 is predicted in the parasite genome. A TgATG4 conditional expression mutant that we have generated is severely affected in growth, and displays significant alterations at the organellar level, noticeably with a fragmentation of the mitochondrial network and a loss of the apicoplast. TgATG4-depleted parasites appear to be defective in the recycling of membrane-bound TgATG8. Overall, our data highlight a role for the TgATG8 conjugation pathway in maintaining the homeostasis of the parasite's organelles and suggest that Toxoplasma has evolved a specialized autophagic machinery with original regulation.

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Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

et al. 2013

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“…For CQ, cytostatic resistance (elevated IC 50 ) is mediated by PfCRT and/or P. falciparum multidrug resistance protein (PfMDR1) mutations that alter the electrochemical potential-driven DV transport of the protonated drug (57,(59)(60)(61)(62)(63) and, hence, access to heme. However, mounting experimental evidence (48,58) suggests the possibility of additional (non-DV) cytocidal targets for this class of drugs, which then predicts the possibility of additional cytocidal resistance mechanisms that are mechanistically distinct from cytostatic resistance mechanisms (64).…”

Section: Discussionmentioning

confidence: 99%

Relative to Quinine and Quinidine, Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum

Gorka

Sherlach

Dios

et al. 2013

Antimicrob Agents Chemother

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The 9-epimers of quinine (QN) and quinidine (QD) are known to exhibit poor cytostatic potency against P. falciparum (Karle JM, Karle IL, Gerena L, Milhous WK, Antimicrob. Agents Chemother. 36:1538 -1544, 1992). We synthesized 9-epi-QN (eQN) and 9-epi-QD (eQD) via Mitsunobu esterification-saponification and evaluated both cytostatic and cytocidal antimalarial activities. Relative to the cytostatic activity of QN and QD, we observed a large decrease in cytostatic activity (higher 50% inhibitory concentration [IC 50

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“…9 This pathogen requires an appropriate host cell environment for its replication and is able to modify its host cell functions. 10 Intuitively, the active modification of host cell growth must be a complex process, as host cells are not inherently programmed to provide an environment conducive to pathogens. 11,12 Host cells have evolved primary lines of defense as countermeasures to pathogen invasion, establishment, and replication.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Toxoplasma Gondii GRA1 Suppresses Host Cell Apoptosis

Chen¹

2017

JBMOA

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Suppression of host cell apoptosis enable Toxoplasma gondii to proliferate, but the mechanism is not well understood. We explore the relationship between the expression of T. gondii dense granule protein 1 (GRA1) and host HeLa cell apoptosis. We inserted the T. gondii gra1 coding gene into a pET32a vector and produced recombinant GRA1 (rGRA1) in E. coli Rosetta strain. We then immunized rabbits with rGRA1 to produce anti-GRA1 serum and infected HeLa cells with T. gondii tachyzoites. We determined the expression of T. gondii GRA1 by Western blotting with anti-GRA1 serum and determined apoptosis of HeLa cells via the Annexin V-FITC/PI method. All the experiments were repeated for three times in the same condition. The expression of GRA1 decreased gradually after T. gondii infection. The rate of HeLa cell apoptosis increased more rapidly in the infected cells than in the uninfected cells. Our results suggest that the suppression of host cell apoptosis is related to the expression of T. gondii GRA1 expression.

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Autophagy in Apicomplexa: a life sustaining death mechanism?

Cited by 44 publications

References 57 publications

Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

Relative to Quinine and Quinidine, Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum

Increased Expression of Toxoplasma Gondii GRA1 Suppresses Host Cell Apoptosis

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