In this section
@article{Tiengwe:2017:10.1371/journal.ppat.1006366,
author = {Tiengwe, C and Bush, PJ and Bangs, JD},
doi = {10.1371/journal.ppat.1006366},
journal = {PLoS Pathogens},
pages = {1--24},
title = {Controlling transferrin receptor trafficking with GPI-valence in bloodstream stage African trypanosomes},
url = {http://dx.doi.org/10.1371/journal.ppat.1006366},
volume = {13},
year = {2017}
}
TY - JOUR
AB - Bloodstream-formAfricantrypanosomesencodetwostructurallyrelatedglycosylphosphati-dylinositol(GPI)-anchoredproteinsthatarecriticalvirulencefactors,variantsurfaceglyco-protein(VSG)forantigenicvariationandtransferrinreceptor(TfR)forironacquisition.Botharetranscribedfromtheactivetelomericexpressionsite.VSGis a GPI2homodimer;TfRisa GPI1heterodimerof GPI-anchoredESAG6andESAG7.GPI-valencecorrelateswithsecretoryprogressionandfatein bloodstreamtrypanosomes:VSG(GPI2) is a surfacepro-tein;truncatedVSG(GPI0) is degradedin thelysosome;andnativeTfR(GPI1) localizesintheflagellarpocket.Tf:Festarvationresultsin up-regulationandredistributionof TfRto theplasmamembranesuggestinga saturablemechanismforflagellarpocketretention.How-ever,becausesuchsurfaceTfRis non-functionalforligandbindingweproposedthatit rep-resentsGPI2ESAG6homodimersthatareunableto bindtransferrin—therebymimickingnativeVSG.Wenowexploita novelRNAisystemforsimultaneouslethalsilencingof allnativeTfRsubunitsandexclusivein-situexpressionof RNAi-resistant TfRvariantswithvalencesof GPI0–2. Ourresultsconformto thevalencemodel:GPI0ESAG7homodimerstraffickto thelysosomeandGPI2ESAG6homodimersto thecellsurface.However,whenexpressedaloneESAG6is up-regulated~7-fold,leavingtheissueof saturableretentionintheflagellarpocketin question.Therefore,wecreatedanRNAi-resistant GPI2TfRheterodi-merbyfusingtheC-terminaldomainof ESAG6to ESAG7.Co-expressionwithESAG6gen-eratesa functionalheterodimericGPI2TfRthatrestoresTf uptakeandcellviability,andlocalizesto thecellsurface,withoutoverexpression.Theseresultsresolvethelongstandingissueof TfRtraffickingunderover-expressionandconfirmGPIvalenceasa criticaldetermi-nantof intracellularsortingin trypanosomes.
AU - Tiengwe,C
AU - Bush,PJ
AU - Bangs,JD
DO - 10.1371/journal.ppat.1006366
EP - 24
PY - 2017///
SN - 1553-7366
SP - 1
TI - Controlling transferrin receptor trafficking with GPI-valence in bloodstream stage African trypanosomes
T2 - PLoS Pathogens
UR - http://dx.doi.org/10.1371/journal.ppat.1006366
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006366
UR - http://hdl.handle.net/10044/1/59659
VL - 13
ER -
Dr. Calvin Tiengwe
Dept. of Life Sciences,
503 Sir Ernst Chain Building,
Imperial College London,
SW7 2AZ, UK
