Exploiting the Achilles' heel of membrane trafficking in trypanosomes

Abstract

Pathogenic protozoa are evolutionarily highly divergent from their metazoan hosts, reflected in many aspects of their biology. One particularly important parasite taxon is the trypanosomatids. Multiple transmission modes, distinct life cycles and exploitation of many host species attests to great prowess as parasites, and adaptability for efficient, chronic infection. Genome sequencing has begun uncovering how trypanosomatids are well suited to parasitism, and recent genetic screening and cell biology are revealing new aspects of how to control these organisms and prevent disease. Importantly, several lines of evidence suggest that membrane transport processes are central for the sensitivity towards several frontline drugs.

Figure 1

The trypanosome endosomal system. A simplified schematic of the trypanosome endomembrane system is shown, with the flagellar pocket at top left. Teal and orange arrows indicate degradative and recycling trafficking routes, blue putative AP-1-mediated transport from the Golgi complex to the lysosome and gray exocytic/biosynthetic pathways. The predominant locations of ISG75, ISG65, aquaglyceroporins and p67 (the major lysosomal protein) are indicated by icons. Evidence suggests that ISG75 is ubiquitylated at, or close to the surface (magenta) and deubiquitylation by TbUsp7 and/or TbVdu1 is proposed to take place before the sorting step at the early endosome that selects for the recycling or degradative arm of the endocytic system. TbVdu1 is known to associate with structures in this region, whilst TbUsp7 is likely cytosolic. AQP2 localization is restricted to the flagellar pocket, while AQP1 and AQP3 are predominantly on the flagellar membrane and plasma membrane, respectively. AQP2 has been recently described as high-affinity pentamidine receptor and this raises the possibility of endocytotic uptake.

Figure 2

Mode of action of trypanocidal drugs. Summary of biochemical pathways linked to drug action for suramin, pentamidine and melarsoprol. Proteins sensitizing to the respective drug, as identified in a genome-wide loss-of-function screen [26^••] are drawn in red. (Pi: inorganic phosphate, Ub: ubiquitin).