Role of calcineurin and actin dynamics in regulated secretion of microneme proteins in<i>Plasmodium falciparum</i>merozoites during erythrocyte invasion

Singh, Shailja; More, Kunal R.; Chitnis, Chetan E.

doi:10.1111/cmi.12177

Cited by 27 publications

(29 citation statements)

References 61 publications

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“…The requirement of calcineurin for the function of host receptor interactions involving PfRh and EBL molecules shows that parasite signal transduction is fundamental to a specific mechanism for host cell recognition by the parasite, independent of invasion ligand release from apical organelles. (Given our findings, a previous report that CsA and FK506 inhibit microneme exocytosis at high concentrations (Singh et al, 2014) might reflect the action of targets secondary to calcineurin.) Previously, the use of inhibitory antibodies showed that PfRh5 synergistically cooperates with the more variably expressed PfRh and EBL-family ligands to promote invasion (Williams et al, 2012), with a more recent study further providing evidence that PfRh5 acts downstream of other PfRh and EBL ligands (Weiss et al, 2015).…”

Section: Discussionsupporting

confidence: 77%

“…To study a possible function for Plasmodium calcineurin near the time of host cell invasion, we considered the drugs FK506 and cyclosporin A, which are each nanomolar inhibitors of physiological, mammalian calcineurin (Fruman et al, 1992). By contrast, both drugs are toxic to P. falciparum only in the micromolar range (Bell et al, 1994; Singh et al, 2014) (Figure S1A), and have been shown to act potently on parasite targets other than calcineurin (Bell et al, 2006). We found that FK506 and cyclosporin A strongly inhibit general parasite development at multiple stages of the intraerythrocytic cell cycle (Figure S1B), precluding their use for assessment of specific parasitic processes.…”

Section: Resultsmentioning

confidence: 99%

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Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans

Paul

Saha

Engelberg

et al. 2015

Cell Host & Microbe

128

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SUMMARY Apicomplexans invade a variety of metazoan host cells through mechanisms involving host cell receptor engagement and secretion of parasite factors to facilitate cellular attachment. We find that the parasite homolog of calcineurin, a calcium-regulated phosphatase complex central to signal transduction in eukaryotes, also contributes to host cell invasion by the malaria parasite Plasmodium falciparum and related Toxoplasma gondii. Using reverse genetic and chemical-genetic approaches, we determine that calcineurin critically regulates and stabilizes attachment of extracellular P. falciparum to host erythrocytes before intracellular entry and has similar functions in host cell engagement by T. gondii. Calcineurin-mediated Plasmodium invasion is strongly associated with host receptors required for host cell recognition and calcineurin function distinguishes this form of receptor-mediated attachment from a second mode of host-parasite adhesion independent of host receptors. This specific role of calcineurin in coordinating physical interactions with host cells highlights an ancestral mechanism for parasitism used by apicomplexans.

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans

Paul

Saha

Engelberg

et al. 2015

Cell Host & Microbe

128

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“…PP2B first garnered attention in apicomplexans because of their sensitivity to Cyclosporin A (CsA) and FK506 (Dobson et al, 1999), two immunosuppressants known to act through calcineurin inhibition in mammalian cells (Jun Liu et al, 1991). Both FK506 and CsA inhibit the secretion of microneme proteins in P. falciparum, suggesting a relationship between calcineurin with the effector(s) of Ca 21 -dependent microneme exocytosis (Singh et al, 2014). Similarly, CsA was shown to block T. gondii egress, which is also dependent on calcium dependent secretion and motility (Moudy et al, 2001).…”

Section: Pp2b Pp5 and Pp7mentioning

confidence: 99%

The serine/threonine phosphatases of apicomplexan parasites

Yang

Arrizabalaga

2017

Molecular Microbiology

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SUMMARY The balance between phosphorylation and de-phosphorylation, which is delicately regulated by protein kinases and phosphatases, is critical for nearly all biological processes. The Apicomplexa are a large phylum which contains various parasitic protists, including human pathogens, such as Plasmodium, Toxoplasma, Cryptosporidium and Babesia species. The diverse life cycles of these parasites are highly complex and, not surprisingly, many of their key steps are exquisitely regulated by phosphorylation. Interestingly, many of the kinases and phosphatases, as well as the substrates involved in these events are unique to the parasites and therefore phosphorylation constitutes a viable target for antiparasitic intervention. Most progress on this realm has come from studies in Toxoplasma and Plasmodium of their respective kinomes and phosphoproteomes. Nonetheless, given their likely importance, phosphatases have recently become the focus of research within the apicomplexan parasites. In this review, we concentrate on serine/threonine phosphatases in apicomplexan parasites, with the focus on comprehensively identifying and naming protein phosphatases in available apicomplexan genomes, and summarizing the progress of their functional analyses in recent years.

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“…It appears that two PfRh proteins, PfRh1 and PfRh5, have distinct functions which are different from the others [15,16]. PfRh1 likely has a role immediately upstream of the alternative-pathway ligands, in signalling the release of micronemes containing EBA-175 [16], a process which is dependent on calcium [17]. While the alternative-pathway EBA and PfRh ligands bind to different erythrocyte receptors, studies with gene knockout parasites, in combination with mutant erythrocytes deficient in particular receptors, have shown that increased expression of some EBAs and PfRhs can functionally compensate for the lack of another [18,19,20].…”

Section: Introductionmentioning

confidence: 99%

Revealing the Sequence and Resulting Cellular Morphology of Receptor-Ligand Interactions during Plasmodium falciparum Invasion of Erythrocytes

et al. 2015

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During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. Understanding each element in this process increases the potential to block the parasite’s life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor-ligand interactions occur in the following sequence with the following cellular morphologies; 1) an early heparin-blockable interaction which weakly deforms the erythrocyte, 2) EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite’s actin-myosin motor, 3) a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4) an AMA1–RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine.

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Role of calcineurin and actin dynamics in regulated secretion of microneme proteins inPlasmodium falciparummerozoites during erythrocyte invasion

Abstract: SummaryPlasmodium falciparum invades host erythrocytes by multiple invasion pathways. The

Cited by 27 publications

References 61 publications

Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans

Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans

The serine/threonine phosphatases of apicomplexan parasites

Revealing the Sequence and Resulting Cellular Morphology of Receptor-Ligand Interactions during Plasmodium falciparum Invasion of Erythrocytes

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