Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance in Trypanosoma brucei

Quintana, J. F. , Bueren-Calabuig, J., Zuccotto, F., de Koning, H. P. , Horn, D. and Field, M. C. (2020) Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance in Trypanosoma brucei. PLoS Neglected Tropical Diseases, 14(7), e0008458. (doi: 10.1371/journal.pntd.0008458) (PMID:32644992) (PMCID:PMC7413563)

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Abstract

Defining mode of action is vital for both developing new drugs and predicting potential resistance mechanisms. Sensitivity of African trypanosomes to pentamidine and melarsoprol is predominantly mediated by aquaglyceroporin 2 (TbAQP2), a channel associated with water/glycerol transport. TbAQP2 is expressed at the flagellar pocket membrane and chimerisation with TbAQP3 renders parasites resistant to both drugs. Two models for how TbAQP2 mediates pentamidine sensitivity have emerged; that TbAQP2 mediates pentamidine translocation across the plasma membrane or via binding to TbAQP2, with subsequent endocytosis and presumably transport across the endosomal/lysosomal membrane, but as trafficking and regulation of TbAQPs is uncharacterised this remains unresolved. We demonstrate that TbAQP2 is organised as a high order complex, is ubiquitylated and is transported to the lysosome. Unexpectedly, mutation of potential ubiquitin conjugation sites, i.e. cytoplasmic-oriented lysine residues, reduced folding and tetramerization efficiency and triggered ER retention. Moreover, TbAQP2/TbAQP3 chimerisation, as observed in pentamidine-resistant parasites, also leads to impaired oligomerisation, mislocalisation and increased turnover. These data suggest that TbAQP2 stability is highly sensitive to mutation and that instability contributes towards the emergence of drug resistance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Quintana, Dr Juan
Creator Roles:
Quintana, J. F.Formal analysis, Investigation, Methodology
de Koning, H. P.Conceptualization, Methodology
Authors: Quintana, J. F., Bueren-Calabuig, J., Zuccotto, F., de Koning, H. P., Horn, D., and Field, M. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN:1935-2727
ISSN (Online):1935-2735
Published Online:09 July 2020
Copyright Holders:Copyright © 2020 Quintana et al.
First Published:First published in PLoS Neglected Tropical Diseases 14(7): e0008458
Publisher Policy:Reproduced under a Creative Commons License

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