CDC50 Orthologues in Plasmodium falciparum Have Distinct Roles in Merozoite Egress and Trophozoite Maturation

Patel, Avnish; Nofal, Stephanie D.; Blackman, Michael J.; Baker, David A.

doi:10.1128/mbio.01635-22

Cited by 10 publications

(14 citation statements)

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“…Deletion of CDC50B does not impair asexual blood stages or gametogenesis. However, two other CDC50 proteins are encoded by Plasmodium , and it is possible that deletion of CDC50B is complemented by another CDC50 protein as suggested in ( 39 ). In support of this hypothesis, it was recently shown in T. gondii that multiple CDC50 proteins interact with the same P4-ATPase ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

“…8). CDC50B is likely involved in GCα folding or trafficking during both stages but its deletion is possibly complemented by another CDC50 protein ( 39 ). GEP1 is only expressed in gametocytes where it is essential for GCα basal activity ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…3E and table S1). This identified GEP1 and also cell division control 50 (CDC50B) that were recently shown to interact with GCα in P. falciparum schizonts (39). CDC50 proteins usually act as chaperones to facilitate activity and/or trafficking of flippases to their final destination (40), suggesting that CDC50B may contribute to the regulation, folding, or trafficking of the predicted flippase domain of GCα.…”

Section: Coimmunoprecipitations Identify a Gcα Membrane Signaling Pla...mentioning

confidence: 97%

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A Plasmodium membrane receptor platform integrates cues for egress and invasion in blood forms and activation of transmission stages

Kuehnel,

Ganga,

Balestra

et al. 2023

Sci. Adv.

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Critical events in the life cycle of malaria-causing parasites depend on cyclic guanosine monophosphate homeostasis by guanylyl cyclases (GCs) and phosphodiesterases, including merozoite egress or invasion of erythrocytes and gametocyte activation. These processes rely on a single GCα, but in the absence of known signaling receptors, how this pathway integrates distinct triggers is unknown. We show that temperature-dependent epistatic interactions between phosphodiesterases counterbalance GCα basal activity preventing gametocyte activation before mosquito blood feed. GCα interacts with two multipass membrane cofactors in schizonts and gametocytes: UGO (unique GC organizer) and SLF (signaling linking factor). While SLF regulates GCα basal activity, UGO is essential for GCα up-regulation in response to natural signals inducing merozoite egress and gametocyte activation. This work identifies a GC membrane receptor platform that senses signals triggering processes specific to an intracellular parasitic lifestyle, including host cell egress and invasion to ensure intraerythrocytic amplification and transmission to mosquitoes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Coimmunoprecipitations Identify a Gcα Membrane Signaling Pla...mentioning

confidence: 97%

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A Plasmodium membrane receptor platform integrates cues for egress and invasion in blood forms and activation of transmission stages

Kuehnel,

Ganga,

Balestra

et al. 2023

Sci. Adv.

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“…Two parasite proteins that likely act upstream of GCα were recently shown to be involved in efficient blood‐stage egress. The membrane protein cell division control protein 50B (CDC50B) was proposed to be required for efficient cGMP synthesis by GCα (Patel et al, 2022), and P. falciparum parasites lacking CDC50B expression took longer to egress. Another protein that was recently shown to act early during blood‐stage egress is the P. falciparum protein phosphatase 1 (PP1) (Paul et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Moving on: How malaria parasites exit the liver

Scheiner,

Burda,

Ingmundson

2023

Molecular Microbiology

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An essential step in the life cycle of malaria parasites is their egress from hepatocytes, which enables the transition from the asymptomatic liver stage to the pathogenic blood stage of infection. To exit the liver, Plasmodium parasites first disrupt the parasitophorous vacuole membrane that surrounds them during their intracellular replication. Subsequently, parasite‐filled structures called merosomes emerge from the infected cell. Shrouded by host plasma membrane, like in a Trojan horse, parasites enter the vasculature undetected by the host immune system and travel to the lung where merosomes rupture, parasites are released, and the blood infection stage begins. This complex, multi‐step process must be carefully orchestrated by the parasite and requires extensive manipulation of the infected host cell. This review aims to outline the known signaling pathways that trigger exit, highlight Plasmodium proteins that contribute to the release of liver‐stage merozoites, and summarize the accompanying changes to the hepatic host cell.

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“…Investigation of the invasion process has indicated that the nascent PVM that surrounds the parasite during and immediately after invasion is derived of host erythrocyte membrane (Geoghegan et al, 2021), but the origin of the phospholipids required for the formation and expansion of the other internal membranes is unclear. The parasite can take up exogenous phospholipids (Moll et al, 1988;Haldar et al, 1989;Fraser et al, 2021;Patel et al, 2022), which the parasites may use to build these compartments, but the parasite also grows in the absence of exogenous phospholipids when the medium is supplemented with fatty acids (Divo et al, 1985;Mitamura et al, 2000;Asahi et al, 2005;Mi-Ichi et al, 2006, 2007Asahi, 2009). Hence, the parasite appears able to fulfil its phospholipid requirement solely with phospholipids that it synthesizes itself (Vial et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Distribution of malaria parasite-derived phosphatidylcholine in the infected erythrocyte

Vallintine

Ooij

2023

Preprint

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Malaria parasites modify their host erythrocyte in multiple ways, leading to changes in the deformability, adhesiveness and permeability of the host erythrocyte. Most of these changes are mediated by proteins exported from the parasite to the host erythrocyte, where these proteins interact with the host cell cytoskeleton or form complexes in the plasma membrane of the infected erythrocyte. In addition, malaria parasites induce the formation of membranous compartments - the parasitophorous vacuole, the tubovesicular network, the Maurer's clefts and small vesicles - within the infected erythrocyte, a cell that is normally devoid of internal membranes. After infection, changes also occur in the composition and asymmetry of the erythrocyte plasma membrane. Although many aspects of the mechanism of export of parasite proteins have become clear, the mechanism by which these membranous compartments are formed and expanded is almost entirely unknown. To determine whether parasite-derived phospholipids play a part in these processes, we applied a metabolic labelling technique that allows phosphatidylcholine to be labelled with a fluorophore. As the host erythrocyte cannot synthesize phospholipids, within infected erythrocytes, only parasite-derived phosphatidylcholine will be labelled with this technique. The results revealed that phosphatidylcholine produced by the parasite is distributed throughout the infected erythrocyte, including the TVN and the erythrocyte plasma membrane, but not Maurer's clefts. Interestingly, labelled phospholipids were also detected in the erythrocyte plasma membrane very soon after invasion of the parasites, indicating that the parasite may add phospholipids to the host erythrocyte during invasion.

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CDC50 Orthologues in Plasmodium falciparum Have Distinct Roles in Merozoite Egress and Trophozoite Maturation

Abstract: Malaria morbidity arises due to successive rounds of replication of Plasmodium parasites within red blood cells. Mature daughter merozoites are released from infected erythrocytes to invade new cells in a tightly regulated process termed egress.

Cited by 10 publications

References 58 publications

A Plasmodium membrane receptor platform integrates cues for egress and invasion in blood forms and activation of transmission stages

A Plasmodium membrane receptor platform integrates cues for egress and invasion in blood forms and activation of transmission stages

Moving on: How malaria parasites exit the liver

Distribution of malaria parasite-derived phosphatidylcholine in the infected erythrocyte

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