Ubiquitination influences suramin efficacy

Suramin is one of the oldest drugs still in use today – it’s been used to treat early stage human African trypanosomiasis caused by T. b. rhodesiense since the early 1920s. Back in 2012 we showed that suramin uptake was dependent on receptor mediated endocytosis and relied on a complex network of proteins from ISG75 in the flagellar pocket to cathepsin-L and MFST in the lysosome (Alsford et al 2012).

We recently contributed to a study led by Prof Mark Field’s group at the University of Dundee, which revealed that two ubiquitin hydrolases (TbUsp7 and TbVdu1) modulate the surface expression and turnover of ISG75 (as well as several other proteins), thereby affecting parasite sensitivity to suramin.

Modulation of the surface proteome through multiple ubiquitylation pathways in African trypanosomes.
PLoS Pathogens 11: e1005236

SILAC analyses revealed that both hydrolases have a high degree of specificity. The effect of TbVdu1 depletion decreases ISG75 and ISG65 protein levels in T. brucei, while loss of TbUsp1 impacts ISG75 and a small cohort of other endosomal proteins, including an orthologue of VAMP7b and MBAP1. These changes in ISG75 protein levels elicited by the loss of either of these regulatory proteins impacts drug efficacy, rendering the parasite significantly less sensitive to suramin.