TY - JOUR
T1 - The role of invariant surface glycoprotein 75 in xenobiotic acquisition by African trypanosomes
AU - Makarov, Alexandr
AU - Began, Jakub
AU - Mautone, Ileana Corvo
AU - Pinto, Erika
AU - Ferguson, Liam
AU - Zoltner, Martin
AU - Zoll, Sebastian
AU - Field, Mark C.
N1 - Funding Information:
JB and SZ were funded by a junior group start-up grant provided by the Institute of Organic Chemistry and Biochemistry (IOCB), CAS, CZ. Work in the Dundee laboratory was funded by the Wellcome Trust (204697/Z/16/Z to MCF). We thank Josef Houser (Central European Institute of Technology, Brno, CZ) and Milan Kozisek (IOCB CAS, Prague, CZ) for their assistance with SPR and ITC measurements. We also thank Anton Popov at the ESRF (BioSAXS beamline BM29, Grenoble, FR) for outstanding beamline support. CIISB, Instruct-CZ Centre of Instruct-ERIC EU consortium, funded by MEYS CR infrastructure project LM2018127, is gratefully acknowledged for the financial support of the measurements at the CF Biomolecular Interactions and Crystallization.
Copyright:
Copyright: © 2023 Makarov et al.
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
KW - invariant surface glycoprotein
KW - trypanosome
KW - suramin
KW - drug metabolism
KW - drug accumulation
KW - CRISPR/Cas9
KW - xenobiotics
UR - http://www.scopus.com/inward/record.url?scp=85159431878&partnerID=8YFLogxK
U2 - 10.15698/mic2023.02.790
DO - 10.15698/mic2023.02.790
M3 - Article
C2 - 36789350
SN - 2311-2638
VL - 10
SP - 18
EP - 35
JO - Microbial Cell
JF - Microbial Cell
IS - 2
ER -