Proteolytic Processing of Nlrp1b Is Required for Inflammasome Activity 英文参考文献.docVIP

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Proteolytic Processing of Nlrp1b Is Required for Inflammasome Activity 英文参考文献.doc

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Proteolytic Processing of Nlrp1b Is Required for Inflammasome Activity 英文参考文献

ProteolyticProcessingofNlrp1bIsRequiredfor InflammasomeActivity BradleyC.Frew,VineetR.Joag,JeremyMogridge* DepartmentofLaboratoryMedicineandPathobiology,UniversityofToronto.Toronto,Ontario,Canada Abstract Nlrp1bisaNOD-likereceptorthatdetectsthecatalyticactivityofanthraxlethaltoxinandsubsequentlyco-oligomerizesinto apro-caspase-1activationplatformknownasaninflammasome.Nlrp1bhastwodomainsthatpromoteoligomerization:a NACHTdomain,whichisamemberoftheAAA+ATPasefamily,andapoorlycharacterizedFunctiontoFindDomain(FIIND). HerewedemonstratethatproteolyticprocessingwithintheFIINDgeneratesN-terminalandC-terminalcleavageproducts ofNlrp1bthatremainassociatedinboththeauto-inhibitedstateandintheactivatedstateaftercellshavebeentreated withlethaltoxin.Functionalsignificanceofcleavagewassuggestedbythefindingthatmutationsthatblockprocessingof Nlrp1balsopreventtheabilityofNlrp1btoactivatepro-caspase-1.ByusinganuncleavedmutantofNlrp1b,weestablished the importance of cleavage by inserting a heterologous TEV protease site into the FIIND and demonstrating that TEV proteaseprocessedthissiteandinducedinflammasomeactivity.ProteolysisofNlrp1bwasshowntoberequiredforthe assembly of a functional inflammasome: a mutation within the FIIND that abolished cleavage had no effect on self- association of aFIIND-CARD fragment, but did reduce therecruitment of pro-caspase-1. Our work indicates that apost- translationalmodificationenablesNlrp1btofunction. Citation:FrewBC,JoagVR,MogridgeJ(2012)ProteolyticProcessingofNlrp1bIsRequiredforInflammasomeActivity.PLoSPathog8(4):e1002659.doi:10.1371/ journal.ppat.1002659 Editor:KennethA.Bradley,UniversityofCaliforniaLosAngeles,UnitedStatesofAmerica ReceivedDecember1,2011;AcceptedMarch6,2012;PublishedApril19,2012 Copyright: ? 2012 Frew et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding:T