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)

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: Quintana, Dr Juan and De Koning, Professor Harry

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 > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• 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