Abstract · Lassa fever virus (LASV) causes severe hemorrhagic fever and is highly endemic in Western Africa, causing 300,000–500,000 ...SkiptomaincontentPNASFebruary8,2011108(6)2396-2401;https://doi.org/10.1073/pnas.1016404108KathrynM.HastieFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteChristopherR.KimberlinFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteMichelleA.ZandonattiFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteIanJ.MacRaeFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteEricaOllmannSaphireFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteForcorrespondence:[email protected],NorthwesternUniversity,Evanston,IL,andapprovedDecember21,2010(receivedforreviewNovember2,2010)ArticleFigures&SIInfo&MetricsPDFAbstractLassafevervirus,amemberofthefamilyArenaviridae,isahighlyendemiccategoryApathogenthatcauses300,000–500,000infectionsperyearinWesternAfrica.ThearenaviralnucleoproteinNPhasbeenimplicatedinsuppressionofthehostinnateimmunesystem,butthemechanismbywhichthisoccurshasremainedelusive.Herewepresentthecrystalstructureat1.5ÅoftheimmunosuppressiveC-terminalportionofLassavirusNPandillustratethat,unexpectedly,its3DfoldcloselymimicsthatoftheDEDDhfamilyofexonucleases.AccompanyingbiochemicalexperimentsillustratethatNPindeedhasapreviouslyunknown,bonafideexonucleaseactivity,withstrictspecificityfordouble-strandedRNAsubstrates.WefurtherdemonstratethatthisexonucleaseactivityisessentialfortheabilityofNPtosuppresstranslocationofIFNregulatoryfactor3andblockactivationoftheinnateimmunesystem.Thus,thenucleoproteinisaviralexonucleasewithanti-immuneactivity,andthisworkprovidesauniqueopportunitytocombatarenaviralinfections.immunologystructuralbiologyvirologyarenavirusLassafevervirus(LASV)causesseverehemorrhagicfeverandishighlyendemicinWesternAfrica,causing300,000–500,000infectionsperyear(1).Initsmostsevereform,L