Diversity in sequence‐dependent control of GRO chemokine mRNA half‐life

[摘要] Neutrophiltraffickingtositesofinjuryorinfectionisregulated,inpart,bythecloselyrelatedGROfamilyofchemokines(CXCL1,‐2,and‐3).ExpressionoftheGROchemokinegenesisknowntobedeterminedbytranscriptionalburstsinresponsetoproinflammatorystimulation,butpost‐transcriptionalmechanismsthatregulatemRNAhalf‐lifearenowrecognizedasimportantdeterminants.mRNAhalf‐lifeisregulatedviadistinctsequencemotifsandsequence‐specific,RNA‐bindingproteins,whosefunctionissubjecttoregulationbyextracellularproinflammatorystimuli.Moreover,suchmechanismsexhibitcell‐typeandstimulusdependency.Wenowpresentevidencethatinnonmyeloidcells,GRO2andGRO3isoformsexhibitatleasttwopatternsofmRNAinstabilitythataredistinguishedbydifferentialsensitivitytospecificmRNA‐destabilizingproteinsandstimulus‐mediatedprolongationofmRNAhalf‐life,respectively.Althoughthe3′UTRregionsofGRO2andGRO3mRNAscontainmultipleAREs,GRO2haseightAUUUApentamers,whereasGRO3hasseven.Theseconferquantitativedifferencesinhalf‐lifeandshowsensitivityforTTPandKSRPbutnotSF2/ASF.Moreover,theseAUUUAdeterminantsdonotconferinstabilitythatcanbemodulatedinresponsetoIL‐1α.Incontrast,IL‐1α‐sensitiveinstabilityforGRO2andGRO3isconferredbysequenceslocatedproximaltothe3′endofthe3′UTRthatareindependentoftheAUUUAsequencemotif.TheseregionsareinsensitivetoTTPandKSRPbutshowreducedhalf‐lifemediatedbySF2/ASF.Thesesequence‐linked,post‐transcriptionalactivitiesprovidesubstantialmechanisticdiversityinthecontrolofGROfamilychemokinegeneexpression...

[学科分类] 生理学

[关键词] gene expression;stability;IL‐1αRNA‐binding proteins