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

BioRxiv : the Preprint Server for Biology
M. HaidarGordon Langsley

Abstract

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 and Plasmodium falciparum infections of bovine leukocytes and human erythrocytes, respectively. 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. When human erythrocytes are infected by P. falciparum they accumulate miR-34c-3p that ablates both prkar2b and parasite Pfpkar mRNA. However, erythrocytes lack protein translation machinery so only miR-34c-3p-mediated loss of Pfpkar transcripts results in an increase in PfPKA kinase activity. Inhibition of miR-34c-3p increases Pfpkar expression to reduce PfPKA activity leading to slowing of intra-erythrocyte parasite development and a reduction in invasion of fresh red blood cells. Finally, we demonstrate that miR-...Continue Reading

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