Global mechanisms for control of the trypanosome proteome: Defining the composition, origins and roles of cullin E3 ligases.

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Parasitic protozoa are major agents of disease, and afflict a major proportion of the global population. In evolutionary terms parasites are highly removed from their hosts, and this is frequently reflected in the presence of unique or unusual mechanisms that underpin their biology. This aspect presents multiple opportunities for the understanding of pathogenesis, the possibility of identifying therapeutic targets as well as offering a fascinating evolutionary perspective on many cellular processes. African trypanosomes are totally reliant on antigenic variation for their longterm survival. The process is so successful that trypanosomes can infect a mammalian host for many months and in some cases years/decades. Additional immune evasion mechanisms, which defend the parasite against components of both the innate and acquired arms of the host immune response, require surface or endosome-located proteins. We have recently made three significant advances in understanding the cell biology that underpins these immune evasion processes; 1. Characterisation of the cell surface proteome, which revealed both remarkable diversity from higher eukaryotes and even from other trypanosomatids such as American trypanosomes, 2. Demonstration of partitioning of surface components into at least four distinct micro-domains - surface, flagellar pocket, flagellum and endosome, with some proteins exhibiting a combination between all four, and 3. Identifying components of the ubiquitylation machinery that control the expression levels of surface proteins. These new insights open a route to understanding how the unique pathogenic surface of African trypanosomes is regulated at the molecular level, together with dissecting how such regulation contributes towards basic biology and pathogenesis. Coupled with this is the means to exploit proteomics technology and insights developed recently to understand in a more global manner regulation of the trypanosome cellular proteome. We propose to interrogate in detail how a group of trypanosome ubiquitin ligases, called cullins, function in this context. Ubiquitin is a major mediator of protein turnover pathways, with the cullin group especially important due to roles in surface receptor turnover and modulation of cell cycle progression. Given the amenability of the trypanosome for genetic manipulation, the comparatively small size of the proteome and the emphasis on post-transcriptional and translation-linked mechanisms to control protein expression levels, we propose that the trypanosome provides a very attractive approach to understand these ubiquitylating complexes, their functional stratification and specificity, in addition to how they contribute towards trypanosome biology and infectivity.