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- Title
Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion.
- Authors
Flueck, Christian; Drought, Laura G.; Jones, Andrew; Patel, Avnish; Perrin, Abigail J.; Walker, Eloise M.; Nofal, Stephanie D.; Snijders, Ambrosius P.; Blackman, Michael J.; Baker, David A.
- 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 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. Phosphodiesterase β (PDEβ) is essential for blood stage development of the malaria parasite. In its absence, phosphorylation of over 200 proteins is adversely affected, revealing PDEβ to be a central regulator that could be targeted with new antimalarial drugs. Author summary: Cyclic nucleotide signalling pathways are ubiquitous in eukaryotes and regulate a plethora of cellular processes. Pathway components include cyclases and phosphodiesterases that synthesise and break down the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP); the signal is translated into a cellular response by effector kinases activated by elevated cyclic nucleotide levels. Malaria parasites deploy cyclic nucleotide signalling to regulate virtually every stage of their complex life cycle. Using a conditional gene knockout approach, we investigate the function of phosphodiesterase β (PDEβ) in the disease-causing blood stage parasites. PDEβ disruption causes a severe reduction in erythrocyte invasion and rapid post-invasion death. Although we show that PDEβ can hydrolyse cAMP and cGMP, both parts of the phenotype are linked to elevated cAMP levels and hyperactivation of PKA. Quantitative phosphoproteomic analysis identified sites that are differentially phosphorylated in the PDEβ knockout, revealing a role for cAMP signalling in cellular processes ranging from chromatin organisation to protein synthesis, as well as the regulation of parasite-specific components of the erythrocyte invasion machinery. In summary, PDEβ disruption causes a profound dysregulation of key events during blood stage replication that could be exploited for the development of new antimalarial drugs.
- Subjects
PLASMODIUM; CYCLIC guanylic acid; CYCLIC adenylic acid; LIFE cycles (Biology); BLOOD parasites
- Publication
PLoS Biology, 2019, Vol 17, Issue 2, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000154