The role of invariant surface glycoprotein 75 in xenobiotic acquisition by African trypanosomes
Authors:Alexandr Makarov1, Jakub Began2,†, Ileana Corvo Mautone1,3, Erika Pinto1, Liam Ferguson1, Martin Zoltner1,4, Sebastian Zoll2 and Mark C. Field1,5
1 School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
2 Laboratory of Structural Parasitology, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, 16610 Prague 6, Czech Republic.
3 Laboratorio de Moléculas Bioactivas, Departamento de Ciencias Biológicas, Universidad de la República, Paysandú 60000, Uruguay.
4 Charles University, Faculty of Science, Department of Parasitology, Vestec, Czech Republic.
5 Institute of Parasitology, Biology Centre, Czech Academy of Sciences, 37005 Ceske Budejovice, Czech Republic.
† Present address: Department of Immunobiology, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
Keywords:
invariant surface glycoprotein, trypanosome, suramin, drug metabolism, drug accumulation, CRISPR/Cas9, xenobiotics.
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Conflict of interest statement:
The authors declare that they have no conflicts of interest.
Please cite this article as:
Alexandr Makarov, Jakub Began, Ileana Corvo Mautone, Erika Pinto, Liam Ferguson, Martin Zoltner, Sebastian Zoll and Mark C. Field (2023). The role of invariant surface glycoprotein 75 in xenobiotic acquisition by African trypanosomes. Microbial Cell 10(2): 18-35. doi: 10.15698/mic2023.02.790
© 2023 Makarov et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
The surface proteins of parasitic protozoa mediate functions essential to survival within a host, including nutrient accumulation, environmental sensing and immune evasion. Several receptors involved in nutrient uptake and defence from the innate immune response have been described in African trypanosomes and, together with antigenic variation, contribute towards persistence within vertebrate hosts. Significantly, a superfamily of invariant surface glycoproteins (ISGs) populates the trypanosome surface, one of which, ISG75, is implicated in uptake of the century-old drug suramin. By CRISPR/Cas9 knockout and biophysical analysis, we show here that ISG75 directly binds suramin and mediates uptake of additional naphthol-related compounds, making ISG75 a conduit for entry of at least one structural class of trypanocidal compounds. However, ISG75 null cells present only modest attenuation of suramin sensitivity, have unaltered viability in vivo and in vitro and no alteration to suramin-invoked proteome responses. While ISG75 is demonstrated as a valid suramin cell entry pathway, we suggest the presence of additional mechanisms for suramin accumulation, further demonstrating the complexity of trypanosomatid drug interactions and potential for evolution of resistance.
doi: 10.15698/mic2023.02.790
Volume 10, pp. 18 to 35, published 27/01/2023.