MicroRNAs (
miRNAs) are small noncoding 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 host cell
protein kinase A (PKA) activity in Theileria annulata-infected bovine leukocytes. We identified prkar2b (
cAMP-dependent protein kinase A type II-beta regulatory subunit) as a novel miR-34c-3p target gene and demonstrate how
infection-induced upregulation of miR-34c-3p repressed PRKAR2B expression to increase PKA activity. As a result, the disseminating tumorlike phenotype of T. annulata-transformed macrophages is enhanced. Finally, we extend our observations to Plasmodium falciparum-parasitized red blood cells, where
infection-induced augmentation in miR-34c-3p levels led to a drop in the amount of prkar2b
mRNA and increased PKA activity. Collectively, our findings represent a novel cAMP-independent way of regulating host cell PKA activity in
infections by Theileria and Plasmodium parasites. IMPORTANCE Small
microRNA levels are altered in many diseases, including those caused by parasites. Here, we describe how
infection by two important animal and human parasites, Theileria annulata and Plasmodium falciparum, induce changes in infected host cell miR-34c-3p levels to regulate host cell PKA
kinase activity by targeting mammalian prkar2b.
Infection-induced changes in miR-34c-3p levels provide a novel epigenetic mechanism for regulating host cell PKA activity independent of fluxes in cAMP to both aggravate
tumor dissemination and improve parasite fitness.