Molecular mechanisms regulating Leishmania life cycle progression

The life cycle of the Leishmania parasite requires transition between insect and mammalian hosts, where temporal cell type differentiation allows adaptation to changing environments. We have recently used CRISPR-Cas9 directed loss-of-function genetic screens to identify a number of Leishmania protein kinases [1] and ubiquitination enzymes [2,3] that are essential for successful differentiation and establishment of infection in the mammalian host, regulating cell signalling and cellular remodelling. We are now tackling two processes that are fundamental to the parasite’s biology: The regulatory mechanism(s) that control cellular remodelling during differentiation and the requirement of co-regulation of the cell cycle and differentiation to enable establishment of infection. To address this we are deciphering the protein kinase-dependent signalling pathways controlled by activators and repressors intrinsic to successful differentiation, as well as the signalling pathways regulating kinetochore assembly during differentiation-induced re-initiation of the cell cycle. We are investigating cellular remodelling through characterisation of E3 ubiquitin ligases essential for differentiation. We expect that the project will provide novel insights into the cross-talk between cell signalling and cellular remodelling through the co-ordinated action of phosphorylation and ubiquitination post-translational modifications.

Funding: Wellcome Trust Investigator Award (2022-2027)

[1] Baker N, Catta-Preta CMC, et al., (2021) Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival. Nat Commun. 12:1244.

[2] Damianou, A, Burge, R, Catta-Preta, MC, Geoghegan, V, Nievas, YR, Newling, K, Brown, E, Burchmore, R, Rodenko B and Mottram, JC (2020) Essential roles for deubiquitination in Leishmania life cycle progression PloS Pathog. 16: e1008455.

[3] Burge, RJ, Damianou, A, Wilkinson, AJ, Rodenko, B and Mottram, JC (2020) Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex. PLOS Pathogens 16: e1008784.