MiRNAs of the Immune System Roles in Inflammation and Cancer01.docx

MiRNAs of the Immune System Roles in Inflammation and Cancer01.docx

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MiRNAsoftheImmuneSystemRolesinInflammationandCancer01

http:

//www.ncbi.nlm.nih.gov/pmc/articles/PMC2876712/?

tool=pubmed

AnnNYAcadSci.Authormanuscript;availableinPMC2011January1.

Publishedinfinaleditedformas:

AnnNYAcadSci.2010January;1183:

183–194.

doi:

10.1111/j.1749-6632.2009.05121.x.

PMCID:

PMC2876712

NIHMSID:

NIHMS201227

CopyrightnoticeandDisclaimer

MiRNAsoftheImmuneSystem:

RolesinInflammationandCancer

JanDavidson-Moncada,1F.NinaPapavasiliou,1*andWayneTam2*

1LaboratoryofLymphocyteBiology,TheRockefellerUniversity,1230YorkAvenue,NewYork,NY10065,USA.

2DepartmentofPathologyandLaboratoryMedicine,WeillCornellMedicalCollege1300YorkAvenue,NewYork,NY10065

Correspondence:

RockefellerUniversity-LymphocyteBiology,1230YorkAveNewYorkNewYork10065,UnitedStates,T:

2123277858,F:

2123277319,Email:

papavasiliou@rockefeller.edu

Thepublisher'sfinaleditedversionofthisarticleisavailableatAnnNYAcadSci

SeeotherarticlesinPMCthatcitethepublishedarticle.

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Abstract

MicroRNAs（miRNAs）aresmallnon-codingRNAsthatregulategeneexpressionbybindingtocomplementarytargetmRNAsandeitherpromotingtheirdecayorinhibitingtheirtranslation.MosteukaryoticgenomesstudiedencodemiRNAs,whichareprocessedfromlonger,non-codingtranscriptsthroughpathwaysconservedfromfungitoplantstoanimals.MiRNAsarenowunderstoodtobekeymediatorsofdevelopmentaltransitionsinanumberofmodelorganisms.Withrespecttotheimmunesystem,miRNAsaffectallfacetsofimmunesystemdevelopment,fromhematopoiesistoactivationinresponsetoinfection,bothduringtheinnateandtheadaptiveimmuneresponse.Atthesametime,miRNAdysregulationisacentraleventinthedevelopmentandpathophysiologyofanumberofcancersoftheimmunesystem.Herewewilldiscussourcurrentunderstandingofthisgeneralregulatorymechanismfocusingonitsinvolvementininflammationandinoncogenesis.

Keywords:

miRNA,immunesystem,inflammation,cancer

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Historically,thesmallRNArevolutionbeganwiththeobservationofanunexplainedsilencingphenomenoninfloralpigmentation.Specifically,overexpressionofapigmentbiosynthesisgeneinpetuniaplants,whichwasexpectedtoproducemorevividlycoloredflowers,resultedinsteadintheproductionofflowerswithvariegatedpigmentationorevencompletelackofcolour.[1]Atthetime,thisphenomenonwastermed“co-suppression”anditisthefirstexampleofwhatisnowknownasRNAinterference.Farfrombeingconfinedtoplants,thisgenesilencingphenomenonwasalsoobservedinfungi[2]andnematodes[3]butthemolecularmechanismbehinditremainedunclearuntilthelandmarkstudiesofFireandMello,whodemonstratedthatitwasspecificallytriggeredbyadouble-strandedRNA.[4]Withinthesamedecade,thefieldofmiRNAbeganwhenlin4,asmallRNAhithertounknownasanmiRNA,wasfoundinC.elegansandnotedtodown-regulateexpressionoflin-14byantisensecomplementaritytothe3’UTRoflin-14.[5,6]ThiskindofRNAwasthenshownnottobeanisolatedpecularitylimitedtonematodes,butratheramemberofalargefamilyofsmallregulatoryRNAparticlesthatiswidelyexpressedinmanyspecies.[7]Sincetheinitialdiscovery,miRNAshavebeencontinuouslyuncoveredandimplicatedinmanycellularprocesses,includingbutnotlimitedtodevelopment,[8,9]cellularproliferation,[10]apoptosisandcancer.[11]ManyhundredsofmiRNAshavebeenidentifiedinhumans,[12]andtheyarepredictedtoregulateapproximately30%ofallmRNAscodingforproteins.[13,14]

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MiRNAbiogenesis

ItisestimatedthatmiRNAscompriseapproximately1%ofthehumangenome.[15]40–70%areencodedinintronsofproteincodinggenesorintronsandexonsofnon-codingRNAs,implyingtwoormorepossiblemechanismsfortheirtranscription.[16]IntronicmiRNAgenesaregenerallythoughttobetranscribedbyRNApolymeraseII;[17]whileexonicmiRNAgenesarethoughttoutilizeRNApolymeraseIIIfortranscription[18].Regardlessofthetranscribingpolymerase,miRNAsareinitiallysynthesizedasprimary-miRNA（pri-miRNA）transcripts,whichcanextendover1kbinlength.ThesetranscriptsareprocessedbyDrosha（aribonuclease[RNase]III）andDGCR8,anRNAbindingprotein,whichcleavethepri-miRNAtoa~70ntprecursor-miRNA（pre-miRNA）withinthenucleus.[17,19,20]Thepre-miRNAisthenexportedoutofthenucleusbyexportin5inthepresenceofitscofactorRanGTP,tobefurtherprocessedinthecytoplasm;concordantly,depletionofExportin5byRNAinterferenceleadstoadecreaseinmaturemiRNAsandadecreaseinpri-orpre-miRNAinthecytoplasm.[21,22]

Onceinthecytoplasmpre-miRNAsarecleavedbyDicer（anRNAendonucleaseIII）alongwithitspartnerproteinTRBP（trans-activatorRNAbindingprotein）toa~21-22ntdoublestrandedRNAmolecule;[23]inhibitionofDicerleadstotheaccumulationofpre-miRNAinthecytoplasm.[24]ThismaturemiRNAmoleculeisloadedontotheRNA-inducedsilencingcomplex（RISC）,whichcontainsDicer,TRBPandanArgonauteproteinthatispresentinmultipleisoformsinmammaliancells.[25,26]WithintheRISCcomplex,thesinglestrandedmaturemiRNAwillguideRISCtothetargetmRNA.[27]Atleastinvertebratesystems,itisthoughtthattargetingofmiRNAsresultsineithertargetRNAdestabilization,[28]orinrepressionoftranslation.[5,29,30]（Figure1）However,recentdatawouldalsosuggestthatundercertainconditions,miRNAbindingleadstoaboostintranslation.[31,32]

Figure1

BiosynthesisofmicroRNA

Primary-microRNA（pri-miRNA）transcriptiontakesplaceinthenucleusbyRNApolymeraseII.Pri-miRNAisthenprocessedinthenucleusbymicroprocessorcomplexcomposedofDroshaandDCGR8,producingaprecursor-miRNAwhichisthenexportedoutofthenucleusbyExportin-5andRan-GTP.Inthecytoplasm,furtherprocessingbyDicerandTRPBreleasesamiRNAduplex.OnestrandisdegradedwhilethematuremiRNAisincorporatedintotheRNA-inducedsilencingcomplex（RISC）,whichleadstotargetingtoanmRNAleadingtoitsdestabilizationorrepressionoftranslation.

MiRNAfunction:

mRNAdestabilizationortranslationalinhibition?

MammalianmiRNAspairtothe3’UTRoftheirtargetmRNA.Itisthoughtthatperfectornear-perfectmatchingofthe5’endofamiRNA（the“seed”region）tothetargetsitewithinthe3’UTRwasthesolerequirementformiRNAsfunctionandledtotranslationalinhibition.Thoughtheideathatseedmatchingleadstointerferencewithtranslationisstillcurrent,thefeatureswithinthe3’UTRofaparticularmRNAthatwouldaccuratelypredictmiRNAtargetinghavebeenexpandedtoincludeproximityofmiRNAbindingsites,AU-richenvironmentsflankingtheseedregionandpreferentialsiteswithintheUTRatbothends.BasedontheseparametersGrimsonandcolleagueshavedevelopedadatabase（www.targetscan.org）tobetterpredictexperimentallyfocusedmiRNA:

mRNApairing.[33]

ItshouldbenotedhoweverthatanalternatepathwayofmiRNA:

targetbindingexists,whichappearstorelyonmatchingofadifferentstretchofsequencewithinthemiRNAtoa3’UTR.Thissecondpathwayisthoughttoleadnottotranslationalinhibitionbutrather,tomRNAdestabilizationthroughARE-mediateddecay.[34]Thesenon-canonicaltypesofmiRNA:

targetinteractionshavenotbeenextensivelystudied,andthuscannotbebioinformaticallypredictedasyet,howevertheycouldbeequallyconsequentialtothebetter-studiedseed-matchingmechanismleadingtotranslationalinhibition.

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miRNAintheImmuneSystem

Theimmunesystemprovidesacomplexbutwellorchestrateddefenseprogrampoisedagainstthemyriadofpathogenicinfectionstowhichanorganismisexposed.Forexample,aninfectionmaytriggeraninflammatoryresponse,theinitiation,propagationandresolutionofwhichmustbecarefullyco-ordinatedandbalanced.Lackofproperinitiationorpropagationhamperstheinnateimmuneresponse;conversely,lackofproperresolutioncanleadtochronicdiseasestates.

Propagationoftheinnateresponseactivatestheadaptiveimmunesystem,whichreliesuponapre-determinedprogramofDNArearrangementsinlymphocytes,togeneratespecificantibodiestowardthepathogenthatinitiatedtheimmuneresponse,aswellasmemory.ThisprocessofDNArearrangementsinlymphocytesisstringentlyregulated;afailureinco-ordinationofcuttingandrepairingtheDNAleadstochromosomaltranslocationsandtheseedsofoncogenesis.

Clearly,theimmuneresponse（bothinnateandadaptive）isextremelyhighlyregulated;recentworkfromanumberoflaboratorieshasrevealedthatmicro-RNAsplayaveryimportantroleinthisintricatesystem（Figure2）.ThefirststeptowardthisunderstandingwastheidentificationofmultiplemiRNAsinhematopoieticcells,manyofwhichwereexpressedspecificallyincellsandtissuesofimmunerelevance.Infact,cellsofthehematopoieticsystemcanbeselectivelyidentifiedfromothertissuesbytheirmiRNAexpressionprofile:

theyallexpressfivehighlyspecificmiRNAs,miR-142,miR-144,miR-150,miR-155andmiR-223.[35]Further,differentlineagesofimmunecellscanalsobedistinguishedbytheiruniquemiRNAexpressionprofiles.ForexampleerythrocytesshowhigherexpressionofmiR-451,whereas,B-andT-LymphocytesexpressmiR-223.[36,37]Additionally,althoughitmayseemthatsimilarexpressionpatternsofmiRNAsexistintwoverydifferentcelltypes,expressionlevels,andspatio-temporalcontrolcanbeverydifferent.Forexample,incomparingBandTlymphocytes,Merekovaetal.reportsimilarexpressionpatternsofmiRNAsinperipheralbloodsamplesofbo