Hierarchical phosphorylation of apical membrane antigen 1 is required for efficient red blood cell invasion by malaria parasites

Prinz, Boris; Harvey, Katherine; Wilcke, Louisa; Ruch, Ulrike; Engelberg, Klemens; Biller, Laura; Lucet, Isabelle S; Erkelenz, Steffen; Heincke, Dorothee; Spielmann, Tobias; Doerig, Christian; Kunick, Conrad; Crabb, Brendan S.; Gilson, Paul R.; Gilberger, Tim‐Wolf

doi:10.1038/srep34479

Cited by 32 publications

(68 citation statements)

References 52 publications

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“…Substitution of AMA1 Ser 610 with an alanine using a conditional transgenic approach led to a dramatic reduction in merozoite invasion [ 54 ]. A later report confirmed the PKA-dependent phosphorylation of AMA Ser 610 , and showed that phosphorylation of Ser 610 is an initial step that is needed before subsequent phosphorylation of Thr 613 by the parasite glycogen synthase kinase 3 (GSK3; PF3D7_0312400) required for efficient invasion [ 103 ]. As mentioned above, a regulatory role for cAMP and PfACβ in calcium release and microneme secretion has been demonstrated using a low K + buffer system [ 5 ].…”

Section: A Role For Pka In Multiple Life-cycle Stages Is Emergingmentioning

confidence: 99%

Cyclic nucleotide signalling in malaria parasites

et al. 2017

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The cyclic nucleotides 3′, 5′-cyclic adenosine monophosphate (cAMP) and 3′, 5′-cyclic guanosine monophosphate (cGMP) are intracellular messengers found in most animal cell types. They usually mediate an extracellular stimulus to drive a change in cell function through activation of their respective cyclic nucleotide-dependent protein kinases, PKA and PKG. The enzymatic components of the malaria parasite cyclic nucleotide signalling pathways have been identified, and the genetic and biochemical studies of these enzymes carried out to date are reviewed herein. What has become very clear is that cyclic nucleotides play vital roles in controlling every stage of the complex malaria parasite life cycle. Our understanding of the involvement of cyclic nucleotide signalling in orchestrating the complex biology of malaria parasites is still in its infancy, but the recent advances in our genetic tools and the increasing interest in signalling will deliver more rapid progress in the coming years.

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Section: A Role For Pka In Multiple Life-cycle Stages Is Emergingmentioning

confidence: 99%

Cyclic nucleotide signalling in malaria parasites

et al. 2017

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“…A role for cyclic GMP (cGMP)–dependent protein kinase (PKG) has been demonstrated in blood stage egress [1, 2] and invasion [3], gametogenesis [4], ookinete motility [5, 6], and sporozoite motility required for invasion of mosquito vector salivary glands and host hepatocytes [7–9]. Available evidence suggests a role for cyclic AMP (cAMP)–dependent protein kinase (PKA) in blood stage invasion [10–12], cell cycle progression [13, 14], anion conductance, and gametocyte deformability [15, 16] as well as regulated exocytosis of sporozoite apical organelles and hepatocyte infectivity [17]. Two recent studies on cAMP signalling in Toxoplasma gondii have shown that absence of one of the three PKA catalytic subunits (PKAc1) leads to premature egress of tachyzoites [18, 19].…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion

et al. 2019

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Cyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Phosphodiesterase (PDE) enzymes are known to control cyclic GMP (cGMP) levels in the parasite, but the mechanisms by which cyclic AMP (cAMP) is regulated remain enigmatic. Here, we demonstrate that Plasmodium falciparum phosphodiesterase β (PDEβ) hydrolyses both cAMP and cGMP and is essential for blood stage viability. Conditional gene disruption causes a profound reduction in invasion of erythrocytes and rapid death of those merozoites that invade. We show that this dual phenotype results from elevated cAMP levels and hyperactivation of the cAMP-dependent protein kinase (PKA). Phosphoproteomic analysis of PDEβ-null parasites reveals a >2-fold increase in phosphorylation at over 200 phosphosites, more than half of which conform to a PKA substrate consensus sequence. We conclude that PDEβ plays a critical role in governing correct temporal activation of PKA required for erythrocyte invasion, whilst suppressing untimely PKA activation during early intra-erythrocytic development.

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“…When EBA175 function is ablated (e.g., genetically), some strains are able to switch to an alternative invasion pathway using the interaction of Rh4 and its receptor CR1 (12). The precise function of each ligand-receptor complex during invasion is largely unknown; however, in recent years, it has become clearer that these interactions do not merely serve for adhesion but, instead, may be involved in transducing signals into either the merozoite (13,14) or potentially the RBC (7).Recently, we attempted to model invasion in terms of the biophysical forces required to enwrap a merozoite toward full RBC entry. Of particular focus were the properties of membrane tension (which, in the RBC, is primarily provided by the cytoskeleton) and bending modulus (the energy required to cause bending of the lipid bilayer) (15).…”

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confidence: 99%

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confidence: 99%

Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion

Koch

Wright

Otto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Invasion of the red blood cell (RBC) by the Plasmodium parasite defines the start of malaria disease pathogenesis. To date, experimental investigations into invasion have focused predominantly on the role of parasite adhesins or signaling pathways and the identity of binding receptors on the red cell surface. A potential role for signaling pathways within the erythrocyte, which might alter red cell biophysical properties to facilitate invasion, has largely been ignored. The parasite erythrocyte-binding antigen 175 (EBA175), a protein required for entry in most parasite strains, plays a key role by binding to glycophorin A (GPA) on the red cell surface, although the function of this binding interaction is unknown. Here, using real-time deformability cytometry and flicker spectroscopy to define biophysical properties of the erythrocyte, we show that EBA175 binding to GPA leads to an increase in the cytoskeletal tension of the red cell and a reduction in the bending modulus of the cell's membrane. We isolate the changes in the cytoskeleton and membrane and show that reduction in the bending modulus is directly correlated with parasite invasion efficiency. These data strongly imply that the malaria parasite primes the erythrocyte surface through its binding antigens, altering the biophysical nature of the target cell and thus reducing a critical energy barrier to invasion. This finding would constitute a major change in our concept of malaria parasite invasion, suggesting it is, in fact, a balance between parasite and host cell physical forces working together to facilitate entry.erythrocyte | malaria | real-time deformability cytometry | flicker spectroscopy | merozoite M alaria infections cause ∼438,000 deaths per year, most of which are due to the protozoan parasite Plasmodium falciparum (1). Although extensive eradication efforts have helped to reduce the incidence of malaria, the spread of drug resistance is a growing concern and novel treatments are urgently needed (2). Throughout the Plasmodium life cycle, parasites shuttle between replicative and motile life-cycle stages, with the motile forms or "zoites" highly adapted to the invasion of host cells. During the blood stages of infection, the merozoite targets and invades the red blood cell (RBC) rapidly (< 30 s) in a process that involves numerous parasite ligands and host cell receptors (3). Merozoite entry is a multistep process commencing with initial attachment and ending with parasite actomyosin-driven invasion (4). Although extensive cellular and molecular details of each step have been elucidated (5, 6), there is still little mechanistic understanding of the role of each protein involved or the signaling events within the erythrocyte that accompany entry (7).Initial attachment to the RBC surface is likely mediated by merozoite surface proteins. Subsequently, the key signaling and strong attachment interactions between host and parasite membranes are thought to be mediated by two major classes of adhesins released either before or concomitant with inva...

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Hierarchical phosphorylation of apical membrane antigen 1 is required for efficient red blood cell invasion by malaria parasites

Cited by 32 publications

References 52 publications

Cyclic nucleotide signalling in malaria parasites

Cyclic nucleotide signalling in malaria parasites

Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion

Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion

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