"Cyclic AMP signaling and evolution of unusual protein kinase A in kinetoplastids”
Stage development and host adaptation of vector transmitted parasites require fast and reliable perception of signals from the host environments. Kinetoplastids share with model eukaryotes second messengers and signaling modules like protein kinases, but their connections, activation mechanisms and interaction in signaling pathways differ mostly from the well investigated models. The second messenger cAMP is important for innate immunity subversion of trypanosomes in the mammalian host1 and for transmission via colonization of the tsetse salivary glands2. We begin to understand the role of the large adenylate cyclase family and a new multi-cyclase regulator (CARP3) in these processes. The cAMP effector protein(s) in this pathway are still elusive. Notably, protein kinase A (PKA), the primary mammalian cAMP effector, has lost its regulation by cAMP. Nucleoside ligands adopted this role3. The structural basis and evolutionary origin of ligand and activation specificity of PKA orthologues and paralogues has been investigated by crystallography, binding assays and a large number of site-directed mutants in vitro and in vivo. The repurposing of PKA for novel ligands and pathways other than cAMP evolved in the Euglenozoa. In T. brucei, PKA is activated by two environmental cues that trigger differentiation: low temperature (cold shock) and carbon source availability. In Leishmania, another unusual PKA isoform tehered to the subpellicular microtubules is essential for maintenance of the elongated shape of promastigotes. Multiple roles in essential adaptive processes in the parasitic life cycle and the unique ligand specificity thus suggest PKA as an attractive target to therapeutically address parasitic diseases caused by kinetoplastids.
1. Salmon, D., Vanwalleghem, G., Morias, Y., Denoeud, J., Krumbholz, C., Lhomme, F., Bachmaier, S., Kador, M., Gossmann, J., Dias, F.B.S., et al. (2012). Adenylate Cyclases of Trypanosoma brucei Inhibit the Innate Immune Response of the Host. Science 337, 463-466. 10.1126/science.1222753.
2. Bachmaier, S., Giacomelli, G., Calvo-Alvarez, E., Vieira, L.R., Van Den Abbeele, J., Aristodemou, A., Lorentzen, E., Gould, M.K., Brennand, A. et al. (2022). A multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission. Nat Commun 13, 5445. 10.1038/s41467-022-33108-z.
3. Bachmaier, S., Volpato Santos, Y., Kramer, S., Githure, G.B., Klockner, T., Pepperl, J., Baums, C., Schenk, R., Schwede, F., Genieser, H.G., et al. (2019). Nucleoside analogue activators of cyclic AMP- independent protein kinase A of Trypanosoma. Nat Commun 10, 1421. 10.1038/s41467-019-09338-z.