Anthrax Edema Toxin Modulates PKA- and CREB-Dependent Signaling in Two Phases 英文参考文献.docVIP

AnthraxEdemaToxinModulatesPKA-andCREB- DependentSignalinginTwoPhases AndreaPuhar1¤*,FedericaDalMolin1,Ste′phanieHorvath1,DanielLadants2,CesareMontecucco1* 1DipartimentodiScienzeBiomedicheSperimentali,Universita`diPadova,Padova,Italy,2Unite′deBiochimiedesInteractionsMacromole′culaires,CNRSURA2185,Institut Pasteur,Paris,France Abstract Background: Anthrax edema toxin (EdTx) is an adenylate cyclase which operates in the perinuclear region of host cells. However, the action of EdTx is poorly understood, especially at molecular level. The ability of EdTx to modulate cAMP- dependent signaling was studied in Jurkat T cells and was compared with that of other cAMP-rising agents: Bordetella pertussisadenylatecyclasetoxin,choleratoxinandforskolin. Methodology/Principal Findings: EdTx caused aprolonged increase of theintracellular cAMP concentration. This led to nuclear translocation of the cAMP-dependent protein kinase (PKA) catalytic subunit, phosphorylation of cAMP response elementbindingprotein(CREB)andexpressionofareportergeneundercontrolofthecAMPresponseelement.Neither p90 ribosomal S6 kinase nor mitogen- and stress-activated kinase, which mediate CREB phosphorylation during T cell activation,wereinvolved.Thedurationofphospho-CREBbindingtochromatincorrelatedwiththespatio-temporalriseof cAMPlevels.Strikingly,EdTxpre-treatedTcellswereunresponsivetootherstimuliinvolvingCREBphosphorylationsuchas additionofforskolinorTcellreceptorcross-linking. Conclusions/Significance:Weconcludedthat,inafirstintoxicationphase,EdTxinducesPKA-dependentsignaling,which culminatesinCREBphosphorylationandactivationofgenetranscription.SubsequentlyCREBphosphorylationisimpaired and therefore T cells are not able to respond to cues involving CREB. The present data functionally link the perinuclear localizationofEdTxtoitsintoxicationmechanism,indicatingthatthisisaspecificfeatureofitsintoxicationmechanism. Citation: Puhar A, Dal Molin F, Horvath S, Ladants D, Montecucco C (2008) Anthrax Edema Toxin M