Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors

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

关键词: immunoglobulin;    plasma cells;    proteostasis;    proteostenosis;   

DOI  :  10.1189/jlb.1011497

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Apreviouslyunsuspected,considerableproportionofnewlysynthesizedpolypeptidesarehydrolyzedrapidlybyproteasomes,possiblycompetingwithendogenoussubstratesandalteringproteostasis.Inviewoftheanti‐cancereffectsofPIs,wesetouttoachieveaquantitativeassessmentofproteasomeworkloadincellshallmarkedbydifferentPIsensitivity,namely,apanelofMMcells,andinadynamicmodelofplasmacelldifferentiation,aprocessthatconfersexquisitePIsensitivity.OurresultssuggestthatproteinsynthesisisakeydeterminantofproteasomalproteolyticburdenandPIsensitivity.IndifferentMMcellsandindifferentiatingplasmacells,theaverageproteolyticworkaccomplishedperproteasomerangesoverdifferentordersofmagnitude,anunexpecteddegreeofvariability,withincreasedworkloadinvariablyassociatedtoincreasedPIsensitivity.Theunfavorableload‐versus‐capacitybalancefoundinhighlyPI‐sensitiveMMlinesisaccountedforbyadecreasedtotalnumberofimmunoproteasomes/cellcoupledtoenhancedgenerationofRDPs.Moreover,indicativeofcause‐effectrelationships,attenuatinggeneralproteinsynthesisbytheotherwisetoxicagentCHXreducesPIsensitivityinactivatedBandinMMcells.OurdatasupporttheviewthatinplasmacellsproteinsynthesiscontributestodeterminePIsensitivitybysaturatingtheproteasomaldegradativecapacity.Quantitatingproteinsynthesisandproteasomeworkloadmaythusprovecrucialtodesignnovelnegativeproteostasisregulatorsagainstcancer...

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