@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}
}

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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  - 

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