SMF-1, SMF-2 and SMF-3 DMT1 Orthologues Regulate and Are Regulated Differentially by Manganese Levels in C. elegans 英文参考文献.docVIP

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SMF-1, SMF-2 and SMF-3 DMT1 Orthologues Regulate and Are Regulated Differentially by Manganese Levels in C. elegans 英文参考文献.doc

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SMF-1, SMF-2 and SMF-3 DMT1 Orthologues Regulate and Are Regulated Differentially by Manganese Levels in C. elegans 英文参考文献

SMF-1,SMF-2andSMF-3DMT1OrthologuesRegulate andAreRegulatedDifferentiallybyManganeseLevelsin C.elegans CatherineAu1,2.,AlexandreBenedetto1,3,8.,JoelAnderson4,ArnaudLabrousse5,6,7,9,KeithErikson4, JonathanJ.Ewbank5,6,7,MichaelAschner1,2,3 * 1Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, United States of America, 2Center for Molecular Toxicology, Vanderbilt University, Nashville, Tennessee,UnitedStatesofAmerica,3Children’sHospital,VanderbiltUniversity,Nashville,Tennessee,UnitedStatesofAmerica,4DepartmentofNutrition,TheUniversity of North Carolina Greensboro, Greensboro, North Carolina, United States of America, 5Centre d’Immunologie de Marseille-Luminy, Universite′ de la Me′diterrane′e, Marseille, France, 6U631, INSERM, Marseille, France, 7UMR6102, CNRS, Marseille, France, 8London Centre for Nanotechnology, University College London, London, UnitedKingdom,9InstitutdePharmacologieetdeBiologieStructurale,Universite′ PaulSabatierToulouseIII,Toulouse,France Abstract Manganese(Mn)isanessentialmetalthatcanexerttoxiceffectsathighconcentrations,eventuallyleadingtoParkinsonism.A majortransporterofMninmammalsisthedivalent-metaltransporter(DMT1).WecharacterizehereDMT1-likeproteinsinthe nematodeC.elegans,whichregulateandareregulatedbyMnandiron(Fe)content.WeidentifiedthreenewDMT1-likegenes inC.elegans:smf-1,smf-2andsmf-3.AllthreecanfunctionallysubstituteforlossoftheiryeastorthologuesinS.cerevisiae.Inthe worm,deletionofsmf-1orsmf-3ledtoanincreasedMntolerance,whilelossofsmf-2ledtoincreasedMnsensitivity.smfmRNA levelsmeasuredbyQRT-PCRwereup-regulateduponlowMnanddown-regulateduponhighMnexposures.TranslationalGFP- fusionsrevealedthatSMF-1andSMF-3stronglylocalizetopartiallyoverlappingapicalregionsofthegutepithelium,suggesting adifferentialroleforSMF-1andSMF-3inMnnutritionalintake.Conversely,SMF-2wasdetectedinthemarginalpharyngeal epithelium,possiblyinvolvedinmetal-sensing.AnalysisofmetalcontentuponMnexposureinsmfmutantsrevealedthatSMF- 3isrequiredfornormal