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ChaperonesmodulateinterferonSignalingPathway ...
Signalingbyinterferon-gammastimulatesanti-viralresponsesandtumorsuppressionthroughtheheterodimericinterferon-gammareceptor.Signalingisinitiatedbybindingofinterferon-gammatoitsreceptor,activatingthereceptor-associatedJAK2tyrosinekinasetophosphorylateSTATtranscriptionfactorsthatactivateinterferonresponsivegenes.Molecularchaperonesthatmodulateoralterproteinfoldinginteractwithdifferentcomponentsoftheinterferonsignalingpathway.OnechaperonethatmodulatesinterferonsignalingishTid-1,amemberoftheDnaJfamilyofchaperonesandacochaperonefortheheatshockproteinHsp70,anothermolecularchaperone.hTid-1wasfoundinatwo-hybridscreentobindtoJAK2andalsotointeractwiththeinterferon-gammareceptor.Inaddition,hTid-1andJAK2alsointeractwithHsp70.OverexpressionofhTid-1repressestranscriptionalactivationbyinterferon-gammaandHsp70dissociatesfromtheseproteinswheninterferonisaddedtocells,suggestingthatHsp70holdsJak2inaninactiveconformationpriortoligandactivation,andisreleasedinthepresenceofagoNISTtoallowtheactivationofJak-2anddownstreampathways.hTid-1andHsp-70interactwithothersignalingproteinsaswell.OneofthisisTax,aproteinencodedbytheHTLV-1virusthatbindstohTid-1.hTid-1alsorepressesNF-kBactivationbyblockingthephosphorylationandinactivationofI-kappaBbytheIkappaBkinasebeta.Hsp70playsasignificantroleinproteinunfoldingforentryintomitochondriaandalsointeractswithtumorsuppressorgeneproductstoproducetheiranti-proliferativeactivity.Oneoftheactionsofinterferonistoinduceapoptosisofinfectedtargetcells,inpartthroughamitochondrialdependentmechanism.AninteractionbetweeninterferonsignalingandHsp70mayalterthismitochondrialapoptosispathway,perhapsplayingaroleininterferon-mediatedapoptosisofinfectedortransformedcells.TheHTLV-1TaxproteinthatinteractswithHsp70blocksmitochondrialinducedapoptosis,providingaprotectionagainstinterferon-mediatedcellulardefenses.
Contributor:KosiGramatikoff,PhD
REFERENCES:ChengH,CenciarelliC,ShaoZ,VidalM,ParksWP,PaganoM,Cheng-MayerC.HumanTcellleukemiavirustype1TaxassociateswithamolecularchaperonecomplexcontaininghTid-1andHsp70.CurrBiol.2001Nov13;11(22):1771-5ChengH,CenciarelliC,TaoM,ParksWP,Cheng-MayerC.HTLV-1Tax-associatedhTid-1,ahumanDnaJprotein,isarepressorofIkappaBkinasebetasubunit.JBiolChem.2002Jun7;277(23):20605-10.JoK,DerinR,LiM,BredtDS.CharacterizationofMALS/Velis-1,-2,and-3:afamilyofmammalianLIN-7homologsenrichedatbrainsynapsesinassociationwiththepostsynapticdensity-95/NMDAreceptorpostsynapticcomplex.JNeurosci.1999Jun1;19(11):4189-99.MireskandariA,ReidRL,KashanchiF,DittmerJ,LiWB,BradyJN.IsolationofaCDNAclone,TRXencodingahumanT-celllymphotrophicvirustype-ITax1bindingprotein.BiochimBiophysActa.1996Apr10;1306(1):9-13.ReynaudC,FabreS,JalinotP.ThePDZproteinTIP-1interactswiththeRhoeffectorrhotekinandisinvolvedinRhosignalingtotheserumresponseelement.JBiolChem.2000Oct27;275(43):33962-8.SarkarS,PollackBP,LinKT,KotenkoSV,CookJR,LewisA,PestkaS.hTid-1,ahumanDnaJprotein,modulatestheinterferonsignalingpathway.JBiolChem.2001Dec28;276(52):49034-42.ThehumanDnaJprotein,hTid-1,enhancesbindingofamultimeroftheherpessimplexvirustype1UL9proteintooris,anoriginofviralDNAreplication.ProcNatlAcadSciUSA.2002Feb19;99(4):1894-8
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