HepatitisBisasmallDNAvirusthatcontainsonly4openreADIngframesinitsgenome.ThreeoftheseORFshavebeenidentifiedastheenvelope,capsidandpolymerasegenes,whilethefunctionofthefourthhasremainedunknownuntilrecently.ThefourthreadingframehasbeencalledtheXgeneandproducesHBxproteinthatisessentialforviralreplicationinlivercellsandactsbroadlytoactivateavarietyoftranscriptionfactors.OnehypothesisofHBxactivityhasbeenthatitentersthenucleustoactasatranscriptionalregulator.OnepieceofevidencesupportingthismechanismofHBxactionisthatHBxinteractswiththetranscriptionfactorCREBandincreasesitsDNA-bindingactivity.ThismechanismdoesnotexplainalloftheeffectsofHBxhowever.AnotherhypothesisfortheHBxmechanismofactionisthatHBxincreasescalciumreleaseintothecytoplasm.ThismechanismofactionisconsistentwiththevarietyoftranscriptionfactorsandkinasesaffectedbyHBxsincecalciumsignalingaffectsmanydifferentsignalingpathways.HBxdoesnotappeartointeractdirectlywithRasorproteinkinasesbutdoesappeartoactivatethecalciumactivateproteinkinasePyk2.AdominantnegativeformofPyk2blocksHBxactivityandtheinvolvementofcalciuminHBxactivationofPyk2isindicatedbytheactionofseveralMolecularprobesthataltercytosoliccalciumsignaling.BAPTA-AMchelatescytosolicandblocksHBxaction.CyclosporinAblocksmitochondrialcalciumsignalingandalsoblockedHBxsignaling.CGP37157isacompoundthatblocksthemitochondrialsodiumcalciumpumpandalsoblockshepatitisBviralreplication,indicatingthatmitochondrialcalciumsignalingisthetargetofHBxfunction.Compoundsthatelevatecytoplasmiccalciumlevels(valinomycinandthapsigargin)increasetherateofreplicationofvirusesthatlackHBx,furthersupportingtheroleofHBxasaninducerofintracellularcalciumsignaling.ThemechanismbywhichHBxcausescalciumreleaseisnotyetknown.SrcactivationappearstoinduceviralreplicationwhileRassignalingdoesnot,suggestingthattheactivationofRassignalingbyHBxmayplayadistinctfunction,perhapstheinductionofcancer.

Contributor:GlennCrostonPh.D.

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