PARP around the Clock

PARP around the Clock

theamphipathichelixofM2would rstcontactacholesterol-richenvironment;thenastheviruscompletesassembly,M2wouldeventuallycontactsurroundingmembraneregionswithlesscholesterol.Atthispoint,M2couldpromotescissionbymodifyingthelinetensionbetweenthebudandthebulkplasmamem-brane(Figure1).Thismechanism,how-ever,reliesonforcesgeneratedattheboundaryoftwolipiddomains.ThisisperhapsnotthecompletestorybecauseM2candrivevesiclebuddinganddetachmentevenfromsimplemodelmembranesthatlacklipidscommonlyinvolvedinestablishingsuchmembranedomains.

Clearly,thestudybyRossmanandcolleaguesmarksonlythebeginningofafascinatingstorythatwillshednewlightonafundamentalbutstillpoorlyunder-stoodstageinthelifecycleofenvelopedviruses.Inaddition,theirstudyidenti esyetanotheressentialfunctionoftheM2channel.ItwillbeinterestingtoseeifM2’sroleinbuddingcanbeexploitedasadrugtargettotreatin uenza.

REFERENCES

Bieniasz,P.D.(2006).Virology344,55–63.Bruce,E.A.,Medcalf,L.,Crump,C.M.,Noton,S.L.,Stuart,A.D.,Wise,H.M.,Elton,D.,Bowers,K.,andDigard,P.(2009).Virology390,268–278.

Carlton,J.G.,andMartin-Serrano,J.(2007).Science316,1908–1912.

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Chen,B.J.,Leser,G.P.,Jackson,D.,andLamb,R.A.(2008).J.Virol.82,10059–10070.

Hurley,J.H.,andHanson,P.I.(2010).Nat.Rev.Mol.CellBiol.11,556–566.

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Rossman,J.S.,Jing,X.,Leser,G.P.,andLamb,R.A.(2010).Cell142,thisissue,902–913.Saksena,S.,Sun,J.,Chu,T.,andEmr,S.D.(2007).TrendsBiochem.Sci.32,561–573.

PARParoundtheClock

VivekKumar1andJosephS.Takahashi1,*

ofNeuroscience,HowardHughesMedicalInstitute,UniversityofTexasSouthwesternMedicalCenter,

5323HarryHinesBoulevard,NA4.118,Dallas,TX75390-9111,USA*Correspondence:joseph.takahashi@utsouthwestern.eduDOI10.1016/j.cell.2010.08.037

1Department

Cellspossessinternal 24hrorcircadianclocksthatsynchronizephysiologicalprocesseswithdailycyclesoflightandnutrientavailability.Inthisissue,Asheretal.(2010) ndthatPARP-1(poly(ADP-ribose)polymerase1)modi escomponentsoftheclockmachineryinresponsetofeeding,providingamechanismforhowmetabolicrhythmscoordinatewithcircadianrhythms.

Manyorganismssynchronizetheirbehavior,physiology,andmetabolismwiththe24hrrotationoftheEarth.Inmammals,amasterpacemakerislocatedinthehypothalamicregioncalledthesuprachiasmaticnucleus(SCN),whichcontainsaclusterof 10,000neurons.EachSCNneuronexpressesatranscrip-tionalfeedbackloopthatself-generatesanoscillationwithaperiodof 24hr(Greenetal.,2008).Cellsinperipheraltissues,suchastheliver,containsimilarcell-autonomousclocks,andtheSCNsynchronizestheoscillationoftheirinternalclockstocoordinaterhythmsthroughoutthebody.However,inboththeSCNandperipheraltissues,themolecularclocksmustintegrateextracel-lularcuestomaintainsynchronywiththe

environment.LightisthedominantcueforthecentralclockintheSCN,butforperipheraltissues,metaboliccycles,suchasfeedingandfasting,canalsoregulatetheinternalclocks.

Thelinkbetweencircadianandmeta-bolicrhythmsisanareaofintensestudybecausedisruptingthesynchronyisthoughttocontributetotheetiologyofdisorderssuchasdiabetes,obesity,andcardiovasculardisease(Greenetal.,2008).Nonetheless,howcircadianandmetabolicsystemsinteractremainslargelyunde ned;inparticular,howfeed-ingdirectlymodulatesthemolecularoscillatorsinperipheraltissueshasbeenamystery.InthisissueofCell,Asheretal.(2010) ndthattheactivityofpoly(ADP-ribose)polymerase1(PARP-1)in

theliverofmiceoscillatesinsynchronywiththefeeding-fastingcycle,providinganewlinkbetweenmetabolismandcirca-dianrhythms.

PARP-1isahighlyconservednuclearproteinthataddschainsofADP-ribosemoleculestoproteinsinaprocesscalledADP-ribosylation(orpolyADP-ribosyla-tion).PARP-1usesnicotinamideadeninedinucleotide(NAD+)tosynthesizethesepolymers,whichcanincludeupto200ADP-riboseunits.Likeotherpost-translationalmodi cations,ADP-ribosyla-tionaltersproteinfunction;chainsofADP-ribosearenegativelycharged,andthustheiradditionisbelievedtodisruptelectrostaticinteractions,suchasthoseinvolvedinDNAbinding.ThemajorsubstrateofPARP-1isitself,and

Cell142,September17,2010ª2010ElsevierInc.841

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