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.doc

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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