Limited specificity of IRF3 and ISGF3 in the transcriptional innate‐immune response to double‐stranded RNA
[摘要] Theinnateimmuneresponseislargelyinitiatedbypathogen‐responsiveactivationofthetranscriptionfactorIRF3.Amongothertargetgenes,IRF3controlstheexpressionofIFN‐β,whichtriggerstheactivationofthetranscriptionfactorISGF3viatheIFNAR.IRF3andISGF3havebeenreportedtocontrolmanyofthesametargetgenesandtogether,controltheantimicrobialinnate‐immuneprogram;however,theirrespectivecontributionsandspecificitiesremainunclear.Here,weusedgenomictechnologiestocharacterizetheirspecificityintermsoftheirphysicalDNA‐bindingandgeneticfunction.WiththeuseofChiP‐seqandtranscriptomicmeasurementsinWTversusifnar−/−versusifnar−/−irf3−/−macrophagesrespondingtointracellulardsRNA,weconfirmedtheknownISGF3DNA‐bindingmotifandfurtherspecifiedadistinctIRF3consensussequence.ThefunctionalspecificityofIRF3isparticularlypronouncedincytokine/chemokineregulation;yet,eveninthecontrolofIFN‐β,thatspecificityisnotabsolute.BymathematicallymodelingIFN‐βproductionwithinanabstractedtissuelayer,wefindthatIRF3versusISGF3specificitymaybecriticaltolimitingIFN‐βproductionandISGF3activation,temporallyandspatially,butthatpartialoverlapintheirspecificityistolerableandmayenhancetheeffectivenessoftheinnate‐immuneresponse...
[发布日期] [发布机构]
[效力级别] [学科分类] 生理学
[关键词] pathogen response;gene expression;interferon;feed‐forward loop;mathematical modeling [时效性]
