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

ABSTRACT: 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 ? (PDE?) 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 PDE?-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 PDE? 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.

SUBMITTER: Flueck C

PROVIDER: S-EPMC6402698 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Flueck Christian C Drought Laura G LG Jones Andrew A Patel Avnish A Perrin Abigail J AJ Walker Eloise M EM Nofal Stephanie D SD Snijders Ambrosius P AP Blackman Michael J MJ Baker David A DA

PLoS biology 20190222 2

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 rapi ...[more]

PMID: 30794532

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Project description:The pathogenicity of the malaria parasites results from their ability to invade and remodel red blood cells (RBCs), expressing antigenic variant proteins for immune evasion and survival, and then to egress from the host cell. These sequential processes require concerted actions of a large number of proteins during the intraerythrocytic developmental cycle (IDC)(Boddey and Cowman, 2013; Cowman et al., 2017; Tan and Blackman, 2021), but the molecular basis of the required regulation is only partially understood. Here, we have characterized an essential Apicomplexan AP2 (ApiAP2) transcription factor (we refer to it as PfAP2-MRP; Master Regulator of Pathogenesis) that shows two peaks of expression during the IDC at 16- and 40-hour post-invasion (h.p.i.). When expression of PfAP2-MRP at 40 h.p.i. was disrupted using an inducible gene knockout approach, ∆PfAP2-MRP parasites unable to form mature merozoites and egress from the host RBCs owing to strong down-regulation of several known egress- and invasion-associated genes, in addition to several novel hypothetical genes thought to be involved in these key life cycle processes. Disruption of PfAP2-MRP expression at 16 h.p.i. results in transcriptional activation of the majority of silenced var genes observed at both bulk and single-cell level. This is also reflected by a significantly higher level of immuno-recognition of the exported proteins on the ∆PfAP2-MRP parasite-infected RBCs by pooled sera from malaria-exposed individuals from an endemic region. In addition, overexpression of many early gametocyte marker genes was also observed in ∆PfAP2-MRP parasites at both 40 h.p.i., and at 16 h.p.i. PfAP2-MRP directly regulates these genes by binding to their promoter region or indirectly through 14 other downstream AP2 transcription factors. Taken together, we conclude that PfAP2-MRP is an upstream transcriptional regulator that participates in mutually exclusive expression patterns shown by the var family of genes and is a critical determinant of parasite's growth during the IDC.

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

Publications

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

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