Characterization of the ATG8-conjugation system in 2<i>Plasmodium</i>species with special focus on the liver stage

Jayabalasingham, Bamini; Voss, Christiane; Ehrenman, Karen; Romano, Julia D.; Smith, Maria Elisa; Fidock, David A.; Bosch, Jürgen; Coppens, Isabelle

doi:10.4161/auto.27166

Cited by 41 publications

(57 citation statements)

References 62 publications

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“…), the single ATG8 homolog localizes to an endosymbiotic nonphotosynthetic plastid, called the apicoplast. 1408,[1451][1452][1453][1454] This organelle is the product of a secondary endosymbiotic event, in which a red alga was endocytosed by an auxotrophic eukaryote (ancestor of an apicomplexan parasite); the apicoplast is the main remnant of this red alga. This organelle is approximately 300 nm in diameter, and is composed of 4 membranes that trace their ancestry to 3 different organisms.…”

Section: Lc3-associated Apicoplastmentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Klionsky¹,

Abdelmohsen²,

Abe³

et al. 2016

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Section: Lc3-associated Apicoplastmentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Klionsky¹,

Abdelmohsen²,

Abe³

et al. 2016

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“…Our current model ( Figure 1A) assumes this pathway to start with signal sequence guided entry into the ER lumen, likely via the Sec61 translocon. Trafficking from the ER to and across the outer apicoplast membrane remains poorly understood, but potentially depends on signals typically involved in endocytosis or autophagy (11)(12)(13) and may take place by more than one route (14,15). Translocation across the periplastid membrane is mediated by machinery evolved from the endosymbiont's ER-associated protein degradation (ERAD) system (1,(16)(17)(18)(19).…”

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confidence: 99%

Toxoplasma gondii Toc75 Functions in Import of Stromal but not Peripheral Apicoplast Proteins

Sheiner

Fellows

Ovciarikova

et al. 2015

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Apicomplexa are unicellular parasites causing important human and animal diseases, including malaria and toxoplasmosis. Most of these pathogens possess a relict but essential plastid, the apicoplast. The apicoplast was acquired by secondary endosymbiosis between a red alga and a flagellated eukaryotic protist. As a result the apicoplast is surrounded by four membranes. This complex structure necessitates a system of transport signals and translocons allowing nuclear encoded proteins to find their way to specific apicoplast sub-compartments. Previous studies identified translocons traversing two of the four apicoplast membranes. Here we provide functional support for the role of an apicomplexan Toc75 homolog in apicoplast protein transport. We identify two apicomplexan genes encoding Toc75 and Sam50, both members of the Omp85 protein family. We localize the respective proteins to the apicoplast and the mitochondrion of Toxoplasma and Plasmodium. We show that the Toxoplasma Toc75 is essential for parasite growth and that its depletion results in a rapid defect in the import of apicoplast stromal proteins while the import of proteins of the outer compartments is affected only as the secondary consequence of organelle loss. These observations along with the homology to Toc75 suggest a potential role in transport through the second innermost membrane.

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“…While a number of proteins involved in apicoplast maintenance have been studied and shown to be essential in T. gondii and Plasmodium spp. (22)(23)(24)29,(32)(33)(34)(35), little is known about the role of proteins that function earlier in the pathway. The autophagy-related protein TgATG9 has previously been shown to be non-essential for survival of T. gondii tachyzoites within the PV in vitro (31).…”

Section: Discussionmentioning

confidence: 99%

ToxoplasmaTgATG9 is critical for autophagy and long-term persistence in tissue cysts

Smith

Kannan

Coppens

et al. 2020

Preprint

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Many of the world's warm-blooded species are chronically infected with Toxoplasma gondii tissue cysts, including up to an estimated one third of the global human population. The cellular processes that permit long-term parasite persistence within the cyst are largely unknown, not only for T. gondii but also for related coccidian parasites that impact human and animal health. A previous study revealed an accumulation of autophagic material in the lysosome-like Vacuolar Compartment (VAC) of chronic stage bradyzoites lacking functional cathepsin L protease (TgCPL) activity. Furthermore, it was shown that TgCPL knockout bradyzoites have compromised viability, indicating the turnover of autophagic material could be necessary for bradyzoite survival. However, the extent to which autophagy itself contributes to bradyzoite development and fitness remained unknown. Herein we show that genetic ablation of TgATG9 substantially reduces canonical autophagy and compromises bradyzoite viability. Transmission electron microscopy revealed structural abnormalities occurring in ∆atg9 bradyzoites, including disorganization of the inner membrane complex and plasma membrane, the occurrence of multiple nuclei within a single bradyzoite cell, as well as various anomalies associated with the VAC. TgATG9-deficient bradyzoites accumulated significantly less undigested material in the VAC upon inhibition of TgCPL activity, suggesting that autophagy contributes material to the VAC for degradation. Intriguingly, abnormal mitochondria networks were observed in TgATG9deficient bradyzoites. They were thin and elongated and often adopted a horseshoe conformation. Some abnormal mitochondrial structures were found to contain numerous different cytoplasmic components and organelles. Bradyzoite fitness was found to be drastically compromised, both in vitro and in mice, with very few brain cysts identified in mice 5 weeks postinfection. Taken together, our data suggests that TgATG9, and by extension autophagy, is critical for cellular homeostasis in bradyzoites and is necessary for long-term persistence within the cyst of this coccidian parasite.

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

Cited by 41 publications

References 62 publications

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Toxoplasma gondii Toc75 Functions in Import of Stromal but not Peripheral Apicoplast Proteins

ToxoplasmaTgATG9 is critical for autophagy and long-term persistence in tissue cysts

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