Dataset Information

Phosphodiesterase beta controls cAMP signalling during malaria parasite erythrocyte invasion

ABSTRACT: Cyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Specific phosphodiesterase (PDE) enzymes are known to control cGMP levels in the parasite, but the mechanisms by with cAMP is regulated remain enigmatic. Here we show that P. falciparum PDEbeta translocates via the ER to an apical location and finally to the plasma membrane of merozoites within the segmented schizont. PDEbeta is essential for blood stage replication, with conditional gene disruption causing a profound invasion phenotype and rapid death of those merozoites that are able to invade a host erythrocyte. Importantly we also demonstrate that PDEbeta is able to hydrolyse both cAMP and cGMP. Loss of PDEbeta activity results in significantly elevated levels of cAMP which correlate temporally with the observed reduction in merozoite invasion. Quantitative phosphoproteomic analysis revealed a >2-fold increase in phosphorylation for >250 phosphosites following silencing of PfPDEbeta. These included a highly significant increase in phosphorylation at PKA substrate consensus sequences. Our results suggest that dysregulated phosphorylation of MyoA S19 and AMA1 S610 likely contributes to the PfPDEbeta knockout invasion phenotype, that PKG activity governs cAMP levels and PKA activation prior to merozoite egress, and that PfPDEbeta has an essential function in regulation cAMP levels in early intra-erythrocytic development in P. falciparum.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human) Plasmodium Falciparum Mad71/papua New Guinea

SUBMITTER: Andrew Jones

LAB HEAD: Bram Snijders

PROVIDER: PXD009157 | Pride | 2019-02-27

REPOSITORIES: Pride

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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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