scholarly journals Correction for Beraki et al., Divergent kinase regulates membrane ultrastructure of the Toxoplasma parasitophorous vacuole

2019 ◽  
pp. 201907987
Keyword(s):  
Parasitophorous Vacuole ◽  
Membrane Ultrastructure

scholarly journals Divergent kinase regulates membrane ultrastructure of theToxoplasmaparasitophorous vacuole

2019 ◽  
Vol 116 (13) ◽  
pp. 6361-6370 ◽  
Author(s):  
Tsebaot Beraki ◽  
Xiaoyu Hu ◽  
Malgorzata Broncel ◽  
Joanna C. Young ◽  
William J. O’Shaughnessy ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Parasitophorous Vacuole ◽  
Parasite Infection ◽  
Secreted Proteins ◽  
Membrane Association ◽  
Membrane Biogenesis ◽  
Active Protein ◽  
Apicomplexan Parasites ◽  
Membrane Ultrastructure ◽  
Binding Loop

Apicomplexan parasites replicate within a protective organelle, called the parasitophorous vacuole (PV). TheToxoplasma gondiiPV is filled with a network of tubulated membranes, which are thought to facilitate trafficking of effectors and nutrients. Despite being critical to parasite virulence, there is scant mechanistic understanding of the network’s functions. Here, we identify the parasite-secreted kinase WNG1 (With-No-Gly-loop) as a critical regulator of tubular membrane biogenesis. WNG1 family members adopt an atypical protein kinase fold lacking the glycine rich ATP-binding loop that is required for catalysis in canonical kinases. Unexpectedly, we find that WNG1 is an active protein kinase that localizes to the PV lumen and phosphorylates PV-resident proteins, several of which are essential for the formation of a functional intravacuolar network. Moreover, we show that WNG1-dependent phosphorylation of these proteins is required for their membrane association, and thus their ability to tubulate membranes. Consequently, WNG1 knockout parasites have an aberrant PV membrane ultrastructure. Collectively, our results describe a unique family ofToxoplasmakinases and implicate phosphorylation of secreted proteins as a mechanism of regulating PV development during parasite infection.

scholarly journals A divergent kinase lacking the glycine-rich loop regulates membrane ultrastructure of theToxoplasmaparasitophorous vacuole

2018 ◽  
Author(s):  
Tsebaot Beraki ◽  
Hu Xiaoyu ◽  
Malgorzata Broncel ◽  
Joanna C. Young ◽  
William J. O’Shaughnessy ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Parasitophorous Vacuole ◽  
Parasite Infection ◽  
Secreted Proteins ◽  
Membrane Association ◽  
Membrane Biogenesis ◽  
Active Protein ◽  
Apicomplexan Parasites ◽  
Membrane Ultrastructure ◽  
Binding Loop

AbstractApicomplexan parasites replicate within a protective organelle called the parasitophorous vacuole (PV). TheToxoplasma gondiiPV is filled with a network of tubulated membranes, which are thought to facilitate trafficking of effectors and nutrients. Despite being critical to parasite virulence, there is scant mechanistic understanding of the network’s functions. Here, we identify the parasite secreted kinase WNG1 as a critical regulator of tubular membrane biogenesis. WNG1 family members adopt an atypical protein kinase fold lacking the glycine rich ATP-binding loop that is required for catalysis in canonical kinases. Unexpectedly, we find that WNG1 is an active protein kinase that localizes to the PV lumen and phosphorylates PV-resident proteins, several of which are essential for the formation of a functional intravacuolar network. Moreover, we show that WNG1-dependent phosphorylation of these proteins is required for their membrane association, and thus their ability to tubulate membranes. Consequently, WNG1 knockout parasites have an aberrant PV membrane ultrastructure. Collectively, our results describe a unique family ofToxoplasmakinases and implicate phosphorylation of secreted proteins as a mechanism of regulating PV formation during parasite infection.

scholarly journals EXP1 is critical for nutrient uptake across the parasitophorous vacuole membrane of malaria parasites

PLoS Biology ◽  
2019 ◽  
Vol 17 (9) ◽  
pp. e3000473 ◽  
Author(s):  
Paolo Mesén-Ramírez ◽  
Bärbel Bergmann ◽  
Thuy Tuyen Tran ◽  
Matthias Garten ◽  
Jan Stäcker ◽  
...  
Keyword(s):  
Nutrient Uptake ◽  
Parasitophorous Vacuole ◽  
Parasitophorous Vacuole Membrane ◽  
Malaria Parasites ◽  
Vacuole Membrane

scholarly journals Plasmodium yoelii Sporozoites with Simultaneous Deletion of P52 and P36 Are Completely Attenuated and Confer Sterile Immunity against Infection

2007 ◽  
Vol 75 (8) ◽  
pp. 3758-3768 ◽  
Author(s):  
Mehdi Labaied ◽  
Anke Harupa ◽  
Ronald F. Dumpit ◽  
Isabelle Coppens ◽  
Sebastian A. Mikolajczak ◽  
...  
Keyword(s):  
Host Cell ◽  
Genetic Manipulation ◽  
Parasitophorous Vacuole ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Mammalian Host ◽  
Electron Microscopic ◽  
Rodent Host ◽  
Blood Stage Infection ◽  
Stage Infection

ABSTRACT Malaria infection starts when sporozoites are transmitted to the mammalian host during a mosquito bite. Sporozoites enter the blood circulation, reach the liver, and infect hepatocytes. The formation of a parasitophorous vacuole (PV) establishes their intracellular niche. Recently, two members of the 6-Cys domain protein family, P52 and P36, were each shown to play an important albeit nonessential role in Plasmodium berghei sporozoite infectivity for the rodent host. Here, we generated p52/p36-deficient Plasmodium yoelii parasites by the simultaneous deletion of both genes using a single genetic manipulation. p52/p36-deficient parasites exhibited normal progression through the life cycle during blood-stage infection, transmission to mosquitoes, mosquito-stage development, and sporozoite infection of the salivary glands. p52/p36-deficient sporozoites also showed normal motility and cell traversal activity. However, immunofluorescence analysis and electron microscopic observations revealed that p52/p36-deficient parasites did not form a PV within hepatocytes in vitro and in vivo. The p52/p36-deficient parasites localized as free entities in the host cell cytoplasm or the host cell nucleoplasm and did not develop as liver stages. Consequently, they did not cause blood-stage infections even at high sporozoite inoculation doses. Mice immunized with p52/p36-deficient sporozoites were completely protected against infectious sporozoite challenge. Our results demonstrate for the first time the generation of two-locus gene deletion-attenuated parasites that infect the liver but do not progress to blood-stage infection. The study will critically guide the design of Plasmodium falciparum live attenuated malaria vaccines.

scholarly journals Sequestration of cholesterol within the host late endocytic pathway restricts liver-stage Plasmodium development

2017 ◽  
Vol 28 (6) ◽  
pp. 726-735 ◽  
Author(s):  
Wiebke Petersen ◽  
Werner Stenzel ◽  
Olivier Silvie ◽  
Judith Blanz ◽  
Paul Saftig ◽  
...  
Keyword(s):  
Parasitophorous Vacuole ◽  
Parasite Burden ◽  
Endocytic Pathway ◽  
Host Cells ◽  
Parasite Development ◽  
Liver Stage ◽  
Niemann Pick ◽  
Development Analysis ◽  
Endocytic Compartments

While lysosomes are degradative compartments and one of the defenses against invading pathogens, they are also hubs of metabolic activity. Late endocytic compartments accumulate around Plasmodium berghei liver-stage parasites during development, and whether this is a host defense strategy or active recruitment by the parasites is unknown. In support of the latter hypothesis, we observed that the recruitment of host late endosomes (LEs) and lysosomes is reduced in uis4− parasites, which lack a parasitophorous vacuole membrane protein and arrest during liver-stage development. Analysis of parasite development in host cells deficient for late endosomal or lysosomal proteins revealed that the Niemann–Pick type C (NPC) proteins, which are involved in cholesterol export from LEs, and the lysosome-associated membrane proteins (LAMP) 1 and 2 are important for robust liver-stage P. berghei growth. Using the compound U18666A, which leads to cholesterol sequestration in LEs similar to that seen in NPC- and LAMP-deficient cells, we show that the restriction of parasite growth depends on cholesterol sequestration and that targeting this process can reduce parasite burden in vivo. Taken together, these data reveal that proper LE and lysosome function positively contributes to liver-stage Plasmodium development.

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