Cyclic AMP signalling controls key components of malaria parasite host cell invasion machinery

Cyclic nucleotides are important signalling molecules across evolution, but their roles in malaria parasites are poorly understood. We have investigated the role of cAMP in asexual blood stage development of Plasmodium falciparum through conditional disruption of adenylyl cyclase (ACβ) and its downstream effector, cAMP-dependent protein kinase (PKA). We show that both production of cAMP and activity of PKA are critical for erythrocyte invasion, whilst key developmental steps that precede invasion still take place in the absence of cAMP-dependent signalling. We also show that another protein with putative cyclic nucleotide binding sites, PfEpac, does not play an essential role in cyclic nucleotide signalling in blood stages. We identify over 2,000 sites whose phosphorylation is dependent on cAMP signalling and we provide mechanistic insight as to how cAMP-dependent phosphorylation of the cytoplasmic domain of the essential invasion adhesin apical membrane antigen 1 (AMA1) controls erythrocyte invasion.