The SUMO protease is important for flagellum biogenesis in Leishmania mexicana.

Mon15  Apr05:57pm(3 mins)
Poster
19
Where:
Renold C2
Speaker:

Authors

M DaalahF HenriquezR Williams
1 university of the west of Scotland , UK

Discussion

Leishmaniasis affects 12 million peoples from 88 tropical countries. Protective and curative treatments is impossible and inadequate respectively with currents drugs being toxic and their overuse have selected resistant parasites. This makes the cases for a rational drug discovery programme to identify novel molecular targets to increase drug specificity, reduce toxicity and efficacious against resistant parasites. Genome differences amongst Leishmania spp cannot account for the three types of leishmaniasis. This suggests that they are regulated Post-translationally or epigenetically. Our aim is to determine if the small ubiquitin-like modifier post translational machinery called SUMOylation is important for parasite development and virulence. We demonstrate that the SUMO protease is situated exclusively in the mitochondria and has conjugating and de-conjugating activities, which are inhibited by selective cysteine protease inhibitors. Overexpression of this protease in aging promastigotes called SUMO-CP produced parasites with retracted flagella, a process which was negated in part, by the cysteine protease inhibitor, N-ETHYLMALEIMIDE (NEM). Generally, parasites with retracted flagellum accumulated sterols in endocytic compartments and are hypersensitive to the sterol inhibitor, ketoconazole. Interestingly, SUMO-CP had equivalent sterol levels as their naïve counterpart and sensitivity to ketoconazole, suggesting that this defect was not due to a defective endocytic trafficking pathway. We now hypothesize that the SUMOylation is vital for flagella biogenesis, the organelle used for attachment, motility, infectivity and preventing macrophages from mounting coordinated attacks to destroy the parasite. We are now generating gene knockout parasites to test if the mutant parasites have disrupted flagella function and elucidate the mechanism through which it occurs. This research has provided new information about the role of the SUMO protease in flagellum biogenesis and virulence, invaluable for the discovery of new anti-leishmanials.

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