miR-34c-3p regulates PKA activity independent of cAMP via ablation of PRKAR2B in Theileria annulata-infected leukocytes and Plasmodium falciparum-infected erythrocytes

MicroRNAs (miRNAs) are small non-coding RNAs that can play critical roles in regulating various cellular processes including during many parasitic infections. Here, we report a regulatory role for miR-34c-3p in cAMP-independent regulation of PKA activity in Theileria annulata infection of bovine leukocytes. We identified prkar2b (cAMP-dependent protein kinase A type II-beta regulatory subunit), as a novel miR-34c-3p target gene and demonstrated how infection-induced up-regulation of miR-34c-3p in leukocytes repressed PRKAR2B expression to increase PKA activity and promote the virulent disseminating tumour phenotype of T. annulata-transformed macrophages. Finally, we demonstrate that miR-34c-3p regulation of prkar2b expression is generalizable, by confirming that Plasmodium falciparum infection of red blood cells also raises intracellular levels of miR-34c-3p and show that this negatively regulates host prkar2b expression so increasing PKA activity. Infection-induced increase in miR-34c-3p levels, therefore, represents a novel cAMP-independent way of regulating host cell PKA activity in infections by Theileria and Plasmodium parasites. Abstract ImportanceTheileria and Plasmodium infections of leukocytes and erythrocytes; respectively, lead to an increase in host cell miR-34c-3p levels and we identified prkar2b (cAMP-dependent protein kinase A type II-beta regulatory subunit), as a specific miR-34c-3p target gene. We demonstrate how infection-induced up-regulation of miR-34c-3p repressed PRKAR2B expression to increase PKA activity independent of fluxes in cAMP. Thus, in two different host-parasite combinations infection-induced increase in miR-34c-3p represents a novel epigenetic way of increasing in host PKA activity that contributes to the pathology of disease.