Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance in Trypanosoma brucei
| العنوان: | Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance in Trypanosoma brucei |
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| المؤلفون: | Harry P. de Koning, Fabio Zuccotto, Juan A. Bueren-Calabuig, Juan F. Quintana, Mark C. Field, David Horn |
| المصدر: | PLoS Neglected Tropical Diseases, Vol 14, Iss 7, p e0008458 (2020) PLoS Neglected Tropical Diseases |
| بيانات النشر: | Public Library of Science, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Glycerol, 0301 basic medicine, RC955-962, Drug Resistance, Drug resistance, Endoplasmic Reticulum, Biochemistry, 0302 clinical medicine, Ubiquitin, Arctic medicine. Tropical medicine, Amino Acids, Protozoans, 0303 health sciences, Secretory Pathway, biology, Protein Stability, Organic Compounds, Chemistry, Monomers, Eukaryota, ER retention, Trypanocidal Agents, Endocytosis, 3. Good health, Cell biology, Infectious Diseases, medicine.anatomical_structure, Drug development, Cell Processes, Physical Sciences, Cellular Structures and Organelles, Basic Amino Acids, Public aspects of medicine, RA1-1270, Aquaglyceroporins, Research Article, medicine.drug, Trypanosoma, Endosome, Trypanosoma brucei brucei, Immunoblotting, 030231 tropical medicine, Glycerol transport, Molecular Probe Techniques, Trypanosoma brucei, Research and Analysis Methods, 03 medical and health sciences, Lysosome, Trypanosoma Brucei, medicine, Animals, Amino Acid Sequence, Molecular Biology Techniques, Molecular Biology, 030304 developmental biology, 030306 microbiology, Lysine, Organic Chemistry, Organisms, Chemical Compounds, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Proteins, Cell Biology, Polymer Chemistry, biology.organism_classification, Parasitic Protozoans, Trypanosomiasis, African, 030104 developmental biology, biology.protein, Lysosomes, Trypanosoma Brucei Gambiense, Pentamidine |
| الوصف: | 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. Author summary Understanding mechanisms that make cells sensitive to xenobiotics (including drugs) is of great importance to both drug development and public health. For the latter, emergence of resistance is particularly important to monitor as well as to predict. Trypanosomes are a major global health burden and for several drugs resistance has emerged and is a considerable concern. Here we have examined the sensitivity to pentamidine, which is mainly mediated by an aquaglyceroporin, a surface channel. We find that the protein is highly sensitive to mutation, rendering the protein unstable, and rendering parasites resistant to pentamidine. As this also includes mutant forms recovered from patients where pentamidine treatment has failed, we suggest that the instability of aquaglyceroporin is an important contributor towards treatment failure. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1935-2727 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::231dae86f1a43df961dfee49d9db039c https://eprints.gla.ac.uk/224645/1/224645.pdf |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....231dae86f1a43df961dfee49d9db039c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19352727 |
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