Instability of aquaglyceroporin (Aqp) 2 contributes to drug resistance in trypanosoma brucei

Juan F. Quintana, Juan Bueren-Calabuig, Fabio Zuccotto, Martin Zoltner, Ricardo Canavate Del Pino, Harry P. de Koning, David Horn, Mark C. Field (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
17 Downloads (Pure)

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 chimerisa-tion with TbAQP3 renders parasites resistant to both drugs. Two models for how TbAQP2 mediates pentamidine sensitivity have emerged; that TbAQP2 mediates pentamidine trans-location across the plasma membrane or via binding to TbAQP2, with subsequent endocyto-sis 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.

Original languageEnglish
Article numbere0008458
Number of pages26
JournalPLoS Neglected Tropical Diseases
Volume14
Issue number7
DOIs
Publication statusPublished - 9 Jul 2020

Keywords

  • Trypanosoma brucei
  • aquaglyceroporin
  • ubiquitylation
  • pentamidine
  • drug resistance

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