We are proud to present collaborative research (Burge et al. PLoS Pathogens 2020, 16: e1008784), between the University of York, University of Glasgow and UbiQ that describes the (essential) roles of ubiquitin proteases (DUBs) and ubiquitin conjugation in Leishmania parasites. Previous studies have investigated the importance of DUBs and the parasite proteasome at various stages of the Leishmania life cycle.* This new study explores the requirement for selected E1, E2 and E3 enzymes across the life cycle of Leishmania. 

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. Burge et al. report on the use of activity-based protein profiling (with our probes Cy5-Ub-PA, UbiQ-072 and Ub-PA, UbiQ-057) and genome engineering to identify deubiquitinating enzymes that are essential for parasite viability or life cycle progression. Characterisation of 28 enzymes of the Leishmania ubiquitination pathway shows 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. Whweras previous studies have investigated the importance of DUBs and the parasite proteasome at various stages of the Leishmania life cycle,* this new study highlights the requirement for selected E1, E2 and E3 enzymes across the life cycle of Leishmania. Overall, ubiquitin enzymes play an important role in Leishmania in vivo infection and they represent potential drug targets in this parasite.

* PLoS Pathog. 2020, 16:e1008455. Nature 2016, 537, 229 and Proc Natl Acad Sci U S A 2019, 116, 9318). 

1. York Biomedical Research Institute and Department of Biology, University of York, United Kingdom,
2. Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom
3. 3 York Biomedical Research Institute and York Structural Biology Laboratory, Department of Chemistry, University of York, United Kingdom
4. UbiQ Bio BV, Amsterdam Science Park, the Netherlands