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