Acylpeptide Hydrolase Inhibition as Targeted Strategy to Induce Proteasomal Down-Regulation 英文参考文献.docVIP
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Acylpeptide Hydrolase Inhibition as Targeted Strategy to Induce Proteasomal Down-Regulation 英文参考文献
AcylpeptideHydrolaseInhibitionasTargetedStrategyto
InduceProteasomalDown-Regulation
GiannaPalmieri1.*,PaoloBergamo2.,AlbertoLuini5,MenottiRuvo3,MartaGogliettino1 ,Emma
Langella3,MicheleSaviano4,RamanathN.Hegde5,AnnamariaSandomenico3,MoseRossi1
1Institute ofProteinBiochemistry, NationalResearchCouncil(CNR-IBP),Napoli, Italy, 2Institute ofFoodSciences,NationalResearchCouncil(CNR-ISA),Avellino,Italy,
3InstituteofBiostructureandBioimaging,NationalResearchCouncil(CNR-IBB),Napoli,Italy,4InstituteofCrystallography,NationalCouncilofResearchofItaly(CNR-IC),
Bari,Italy,5TelethonInstituteofGeneticsandMedicine(TIGEM),Napoli,Italy
Abstract
Acylpeptide hydrolase (APEH), one of the four members of the prolyl oligopeptidase class, catalyses the removal of N-
acylated amino acids from acetylated peptides and it has been postulated to play a key role in protein degradation
machinery. Disruption of protein turnover has been established as an effective strategy to down-regulate the ubiquitin-
proteasome system (UPS) and as a promising approach in anticancer therapy. Here, we illustrate a new pathway
modulatingUPSandproteasomeactivitythroughinhibitionofAPEH.Tofindnovelmoleculesabletodown-regulateAPEH
activity,wescreenedasetofsyntheticpeptides,reproducingthereactive-siteloopofaknownarchaealinhibitorofAPEH
(SsCEI),andtheconjugatedlinoleicacid(CLA)isomers.A12-merSsCEIpeptideandthetrans10-cis12isomerofCLA,were
identifiedasspecificAPEHinhibitorsandtheireffectsoncell-basedassayswereparalleledbyadose-dependentreduction
ofproteasomeactivityandtheactivationofthepro-apoptoticcaspasecascade.Moreover,celltreatmentwiththeindividual
compoundsincreasedthecytoplasmlevelsofseveralclassichallmarksofproteasomeinhibition,suchasNFkappaB,p21,
andmisfoldedorpolyubiquitinylatedproteins,andadditiveeffectswereobservedincellsexposedtoacombinationofboth
inhibitorswithoutanycytotoxicity.Remarkably,transfectionofhumanbronchialepithelialcellswithAPEHsiRNA,promoted
amarkedaccumulationofamutantofthecysticfibrosist
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