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

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