Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

TY - JOUR

T1 - Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

AU - Baker, Nicola

AU - Glover, Lucy

AU - Munday, Jane C.

AU - Andres, David Aguinaga

AU - Barrett, Michael P.

AU - de Koning, Harry P.

AU - Horn, David

PY - 2012/7/3

Y1 - 2012/7/3

N2 - African trypanosomes cause sleeping sickness in humans, a disease that is typically fatal without chemotherapy. Unfortunately, drug resistance is common and melarsoprol-resistant trypanosomes often display cross-resistance to pentamidine. Although melarsoprol/pentamidine cross-resistance (MPXR) has been an area of intense interest for several decades, our understanding of the underlying mechanisms remains incomplete. Recently, a locus encoding two closely related aquaglyceroporins, AQP2 and AQP3, was linked to MPXR in a high-throughput loss-of-function screen. Here, we show that AQP2 has an unconventional "selectivity filter." AQP2-specific gene knockout generated MPXR trypanosomes but did not affect resistance to a lipophilic arsenical, whereas recombinant AQP2 reversed MPXR in cells lacking native AQP2 and AQP3. AQP2 was also shown to be disrupted in a laboratory-selected MPXR strain. Both AQP2 and AQP3 gained access to the surface plasma membrane in insect life-cycle-stage trypanosomes but, remarkably, AQP2 was specifically restricted to the flagellar pocket in the bloodstream stage. We conclude that the unconventional aquaglyceroporin, AQP2, renders cells sensitive to both melarsoprol and pentamidine and that loss of AQP2 function could explain cases of innate and acquired MPXR.

AB - African trypanosomes cause sleeping sickness in humans, a disease that is typically fatal without chemotherapy. Unfortunately, drug resistance is common and melarsoprol-resistant trypanosomes often display cross-resistance to pentamidine. Although melarsoprol/pentamidine cross-resistance (MPXR) has been an area of intense interest for several decades, our understanding of the underlying mechanisms remains incomplete. Recently, a locus encoding two closely related aquaglyceroporins, AQP2 and AQP3, was linked to MPXR in a high-throughput loss-of-function screen. Here, we show that AQP2 has an unconventional "selectivity filter." AQP2-specific gene knockout generated MPXR trypanosomes but did not affect resistance to a lipophilic arsenical, whereas recombinant AQP2 reversed MPXR in cells lacking native AQP2 and AQP3. AQP2 was also shown to be disrupted in a laboratory-selected MPXR strain. Both AQP2 and AQP3 gained access to the surface plasma membrane in insect life-cycle-stage trypanosomes but, remarkably, AQP2 was specifically restricted to the flagellar pocket in the bloodstream stage. We conclude that the unconventional aquaglyceroporin, AQP2, renders cells sensitive to both melarsoprol and pentamidine and that loss of AQP2 function could explain cases of innate and acquired MPXR.

KW - transporter

KW - major instrinsic proteins

KW - aquaporin

KW - DRUG-RESISTANCE

KW - CROSS-RESISTANCE

KW - WATER CHANNEL

KW - NUCLEOSIDE TRANSPORTER

KW - ADENOSINE TRANSPORTER

KW - DIMINAZENE ACETURATE

KW - BRUCEI-BRUCEI

KW - DIAMIDINE DRUGS

KW - EXPRESSION

KW - Trypanosoma brucei

KW - trypanosomiasis

KW - BLOOD-STREAM FORM

UR - https://www.scopus.com/pages/publications/84863585771

U2 - 10.1073/pnas.1202885109

DO - 10.1073/pnas.1202885109

M3 - Article

SN - 0027-8424

VL - 109

SP - 10996

EP - 11001

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 27

ER -