Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex.

Collaborative research between the University of York, University of Glasgow and UbiQ looks into the (essential) roles of ubiquitin proteases (DUBs) and ubiquitin conjugation in Leishmania parasites.

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. This disease, which has a tropical and sub-tropical distribution, is transmitted by the bite of a sandfly and causes around 70,000 deaths annually. Leishmania parasites need a variety of protein degradation pathways to allow the parasite to transition through the various life cycle stages that occur in its insect and mammalian hosts. Damianou et al. report on the use of activity-based protein profiling (using probes Cy5-Ub-PA, UbiQ-072 and Ub-PA, UbiQ-057) and genome engineering to identify DUBs that are essential for parasite viability or life cycle progression. Burge et al. report on the characterisation of 28 enzymes of the Leishmania ubiquitination pathway and show that many are required for life cycle progression or infection. The proteins UBC2 and UEV1 were studied in more depth because of their importance in the promastigote to amastigote transition. X-ray crystal structure analysis showed these proteins to form a heterodimer with a highly conserved interface. Whereas the UbC2-UEV1 dimer forms K63 linked diubiquitin chains (in vitro), UBC2 can also co-operate in vitro with human E3 enzymes (RNF8 and BIRC2) to form (non-K63-linked) polyubiquitin chains. Overall, ubiquitin enzymes play an important role in Leishmania in vivo infection and they represent potential drug targets in this parasite.

Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex
Rebecca J. Burge, Andreas Damianou, Anthony J. Wilkinson,  Boris Rodenko, Jeremy C. Mottram

Now published in PLOS Pathogens doi: 10.1371/journal.ppat.1008784