Endogenous and exogenous pathways maintain the reductive capacity of the phagosome

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: redox;    reductase;    proteolysis;    endosome;    lysosome;   

DOI  :  10.1189/jlb.2HI0315-083R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Althoughendosomes,lysosomes,andphagosomesrequireareductiveenvironmentfortheoptimalactivityofdisulfidereductasesandotherthiol‐dependentenzymes,howthesereductiveenvironmentsareestablishedandmaintainedremainunknown.Ourgoalinthisstudywastobegintoelucidatetheredoxcontrolsystemsresponsibleformaintainingredox‐sensitiveenzymaticactivitiesinthephagolysosomeofmurinemacrophages.Throughtheuseofspecificinhibitorsandgeneticknockdownofknownredoxenzymes,weidentifiedredoxpathwaysthatinfluencephagosomaldisulfidereduction.Inparticular,knowninhibitorsoftheNADPH‐dependentselenoprotein,thioredoxinreductase,wereshowntoinhibitphagosomaldisulfidereductionandphagosomalproteolysis.ThiswassupportedbytheobservationthatconditionaldeletionoftheselenocysteinetRNAinmacrophagesdecreasedphagosomaldisulfidereductioncapacity.Inaddition,pharmacologicinhibitionofthepentosephosphatepathwaydecreasedratesofdisulfidereductionandproteolysisinthephagosome,implicatingNADPHasasourceofphagosomalreductiveenergy.Finally,byanalyzingtheeffectofextracellularredoxcouples,suchascysteine:cystineonthiol‐dependentphagosomalprocesses,wedemonstratedthattheextracellularspacecanadditionallysupplythephagosomewithreductiveenergy.Collectively,thesedatademonstratethatdefinedcytosolicreductivepathwaysactinconcertwiththeuptakeofcysteinefromtheextracellularspacetosupportthiol‐dependentchemistriesinthephagosome...

【 授权许可】

CC BY