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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
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