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Metabolic Regulation of Protein N-Alpha-Acetylation by Bcl-xL Promotes Cell Survival

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MetabolicRegulation

ofProteinN-Alpha-Acetylation

byBcl-xLPromotesCellSurvival

CarolineH.Yi,1HelingPan,1,11JanSeebacher,1,11Il-HoJang,4,11SvenG.Hyberts,2GregoryJ.Heffron,2MatthewG.VanderHeiden,3,7,8RenliangYang,9FupengLi,9JasonW.Locasale,3HadarSharfi,3BoZhai,1RicardRodriguez-Mias,2HarryLuithardt,10LewisC.Cantley,3,5,6GeorgeQ.Daley,4JohnM.Asara,5,6StevenP.Gygi,1GerhardWagner,2Chuan-FaLiu,9andJunyingYuan1,*

1DepartmentofCellBiology2DepartmentofBiologicalChemistryandMolecularPharmacology3DepartmentofSystemsBiology4Children’sHospitalBoston5DivisionofSignalTransductionBethIsraelDeaconessMedicalCenter,Boston,MA02115,USA6DepartmentofMedicine7DanaFarberCancerInstituteHarvardMedicalSchool,Boston,MA02115,USA8KochInstitute,MassachusettsInstituteofTechnology,Cambridge,MA02142,USA9DivisionofChemicalBiologyandBiotechnology,SchoolofBiologicalSciences,NanyangTechnologicalUniversity,60NanyangDrive,Singapore637551,RepublicofSingapore10SolutionsLabs,400TechnologySquare,Cambridge,MA02139,USA11Theseauthorscontributedequallytothiswork*Correspondence:jyuan@hms.harvard.eduDOI10.1016/j.cell.2011.06.050

SUMMARY

Previousexperimentssuggestaconnectionbetween

theN-alpha-acetylationofproteinsandsensitivity

ofcellstoapoptoticsignals.Here,wedescribe

abiochemicalassaytodetecttheacetylationstatus

ofproteinsanddemonstratethatproteinN-alpha-

acetylationisregulatedbytheavailabilityofacetyl-

CoA.BecausetheantiapoptoticproteinBcl-xLis

knowntoinfluencemitochondrialmetabolism,we

reasonedthatBcl-xLmayprovidealinkbetween

proteinN-alpha-acetylationandapoptosis.Indeed,

Bcl-xLoverexpressionleadstoareductioninlevels

ofacetyl-CoAandN-alpha-acetylatedproteinsin

thecell.ThiseffectisindependentofBaxandBak,

theknownbindingpartnersofBcl-xL.Increasing

cellularlevelsofacetyl-CoAbyadditionofacetate

orcitraterestoresproteinN-alpha-acetylationin

Bcl-xL-expressingcellsandconferssensitivityto

apoptoticstimuli.Weproposethatacetyl-CoAserves

asasignalingmoleculethatcouplesapoptoticsensi-

tivitytometabolismbyregulatingproteinN-alpha-

acetylation.

INTRODUCTION

Increasingevidencesuggeststhatspecificmetabolicalterations

associatedwithcancercellsmaynotbeancillarytotheirtrans-formationbutareinstrumentaltotheirtumorigenicpotentialby

mediatingcellproliferation,growth,andsurvival(VanderHeiden

etal.,2009).Manyoncogenesandtumorsuppressorgenes

knowntopromoteexcesscellproliferationalsoalterbiosyn-

thetic(oranabolic)processes.Forexample,Aktexpression

stimulatesglucoseuptakeandglycolysis,thepentosephos-

phatepathway,andfattyacidsynthesis.c-Mycexpression

promotesglutaminemetabolismaswellaspurineandpyrimidine

biosynthesis.Furthermore,mutationsingenesencodingmeta-

bolicenzymeshavebeenidentifiedbycancergeneticassocia-

tionstudies(VanderHeidenetal.,2009).Howspecificmetabo-

litescontributetoincreasedproliferationandapoptotic

resistanceintumorcellsremainsacentralunansweredquestion.

Theproto-oncogeneBcl-xLhasaprominentroleinpromoting

cellsurvivalandcancerdevelopment(Boiseetal.,1993).Itis

wellestablishedthatBcl-xLprotectsagainstapoptosisby

directlybindingandinhibitingBax/Bakoligomerization-medi-

atedmitochondrialpermeabilization.However,certainBcl-xL

mutants,suchasF131V/D133AandG148E,thatareunableto

bindtoBaxorBak,neverthelessretain70%–80%antiapoptotic

activityofWTBcl-xL(Chengetal.,1996).Curiously,Bcl-xLhas

alsobeenshowntoregulatemitochondrialrespirationand

metabolism(Gottliebetal.,2000;VanderHeidenetal.,1999).

WhetherthemetabolicfunctionofBcl-xLcontributestoitsrole

inmediatingapoptoticresistanceisunclear.

OurunexpectedidentificationofanN-terminalacetyltransfer-

ase,ArrestDefective1(dARD1),inagenome-wideRNAinterfer-

ence(RNAi)screeninDrosophilacellsforapoptoticregulators

(Yietal.,2007)promptedustopositthatproteinN-alpha-acety-

lation,amajorN-terminalmodification,linkscell

metabolism

Cell146,607–620,August19,2011ª2011ElsevierInc.607toapoptoticinductionincancercells.SincedARD1isepistatic

todiap1,whichencodesforadirectinhibitorofcaspasesin

Drosophila,andARD1isrequiredforcaspaseactivationin

mammaliancells(Yietal.,2007),theroleforARD1inmediating

caspaseactivationisevolutionarilyconserved.HowARD1

regulatescaspaseactivationhasnotyetbeenillustrated.

Inmammaliancells,proteinN-alpha-acetylationismediated

bythehighlyconservedN-acetyltransferaseproteincomplexes

(NatA,NatB,NatC,NatD,andNatE).TheNatAcomplex

consistsofthecatalyticsubunit,ArrestDefective1(hNaa10p/

ARD1),andtheauxiliarysubunit,N-acetyltransferase1(NAT1/

hNaa15p/NATH),whereasNatBconsistsofN-terminalacetyl-

transferase3(hNaa20p/NAT3)andmitochondrialdistribution

andmorphology20(hNaa25p/Mdm20).AlthoughtheNatcom-

plexesareimplicatedinregulatingcell-cycleprogression,

cellproliferation,andtumorigenesis,themechanismsthat

connectN-alpha-acetylationtothecellularproteinapparatus

合集下载

INT J BIOCHEM CELL B-IF4.804

INT J BIOCHEM CELL B-IF4.804

TheInternationalJournalofBiochemistry&CellBiology38(2006)

671–683

Overexpressionofthenovelhumangene,nuclear

apoptosis-inducingfactor1,inducesapoptosis

BingfengLva,b,1,TaipingShic,1,XinyuWangc,QuanshengSonga,

YingmeiZhangb,YanShenc,d,DalongMaa,b,c,YaxinLoub,c,d,∗

aLabofMedicalImmunology,SchoolofBasicMedicalScience,HealthScienceCenter,PekingUniversity,38XueyuanRoad,Beijing100083,ChinabCenterforHumanDiseaseGenomics,PekingUniversity,38XueyuanRoad,Beijing100083,ChinacChineseNationalCenterofHumanGenomeResearch(Beijing),3NorthYongchangRoad,BDA,Beijing100176,ChinadNationalLaboratoryofMedicalMolecularBiology,InstituteofBasicMedicalSciences,ChineseAcademyofMedicalSciences/PekingUnionMedicalCollege,Beijing100730,China

Received8August2005;receivedinrevisedform11November2005;accepted14November2005Availableonline9December2005

蛋白质翻译后修饰研究进展

蛋白质翻译后修饰研究进展

收稿日期: 2011-02-24

作者简介: 郭会灿，女，硕士，讲师，研究方向: 生物制药; E-mail: hedongyang1983@126． com 蛋白质翻译后修饰研究进展

郭会灿

( 石家庄职业技术学院化学工程系，石家庄050081)

[摘 要]: 翻译后修饰在蛋白质加工、成熟的过程中发挥着重要的作用，它可以改变蛋白质的物理、化学性质，影响蛋白质的空间构象、立体位阻及其稳定性，进而对蛋白质的生物学活性产生作用，引起蛋白质的功能改变。修饰基团自身的结构特性对蛋白质的性质、功能也会产生深远的影响。在已有的研究基础上，综述蛋白质翻译后修饰的主要类型以及各修饰作用潜在的生物学功能。

[关键词]: 蛋白质翻译后修饰 糖基化 乙酰化 泛素化 磷酸化

生命有机体是一个复杂、动态的系统，时刻进行着不断的新陈代谢，产生新物质、清除废物质及有害物质、协调各个部位间的功能发挥。偶尔该系统也会发生紊乱，引发各种异常功能，出现疾病的症状。而这所有的一切都依赖于生物大分子蛋白质。蛋白质是机体内各种功能的执行者，如机体免疫、细胞凋亡、信号转导、刺激反应及个体发育等。蛋白质功能的正常发挥决定着有机体能否有序、高效的进行。

体内基因表达产物的正确折叠、空间构象的正确形成决定了蛋白质的正常功能，而翻译后修饰在这个成熟过程中发挥着重要的调节作用。因为翻译后修饰使蛋白质的结构更为复杂，功能更为完善，调节更为精细，作用更为专一。并且细胞内许多蛋白质的功能也是通过动态的蛋白质翻译后修饰来调控的; 细胞的许多生理功能，例如细胞对外界环境的应

答［1，2］，也是通过动态的蛋白质翻译后修饰来实现的。正是这种蛋白质翻译后修饰的作用，使得一个基因并不只对应一个蛋白质，从而赋予生命过程更多的复杂性。因此，阐明蛋白质翻译后修饰的类型、机制及其功能对保障生命有机体的正常运转，预防、治疗相关的疾病有着重要意义。

学习笔记之基因功能分类参阅文章

学习笔记之基因功能分类参阅文章

基因功能分类

Apoptosis Panel for Monitoring Cell Programmed Death and Survival:

TNF Ligand Family:

LTA, LTB, TNF, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9,

TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15,

TNFSF18. TNF Receptor Family:

LTBR, TNFRSF1A, TNFRSF1B, TNFRSF4, TNFRSF5, TNFRSF6, TNFRSF6B,

TNFRSF7, TNFRSF8, TNFRSF9, TNFRSF10A, TNFRSF10B, TNFRSF10C,

TNFRSF10D, TNFRSF11A, TNFRSF11B, TNFRSF12, TNFRSF14, TNFRSF17,

TNFRSF18, TNFRSF21.

Bcl-2 Family: BAD, BAG1, BAG3, BAG4, BAK1, BAX, BBC3, BCL2, BCL2A1,

BCL2L1, BCL2L11, BCL2L2, BIK, BLK, BNIP3, BOK, HRK, MCL1.

Caspase Family: CASP1, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8,

CASP9, CASP10, CASP13, CASP14.

IAP Family: BIRC1, BIRC2, BIRC3, BIRC4, BIRC5, BIRC6.

TRAF Family: TANK, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRIP.

两色金鸡菊黄酮及主成分对高糖软脂酸诱导H1ZY-1细胞能量代谢紊乱的调控作..

两色金鸡菊黄酮及主成分对高糖软脂酸诱导H1ZY-1细胞能量代谢紊乱的调控作..

中英文缩略词对照表英文缩写英文全名中文译名DNDiabetesNephropathy糖尿病肾病PBSPhosphateBufferedSaline磷酸盐缓冲溶液ROSReactiveOxygenSpecies活性氧ECMExtraCellularMatrix细胞外基质AMPKAMP-activatedproteinkinase腺苷酸活化蛋白激酶FCFlavonoidsofCoreopsistinctoriaNutt.两色金鸡菊黄酮纯化物ICAM-1intercellularadhesionmolecules-1细胞间黏附分子1MCP-1MonocyteChemoattractantProtein-1人单核细胞趋化蛋白-1SREBP1sterolregulatoryelement-bindingprotein-1甾醇调节元件结合蛋白1ACC1AcetylCoenzymeACarboxylase1乙酰辅酶a羧化酶1eNOSendothelialNitricOxideSynthase一氧化氮合酶NOX4Nicotinamideadeninedinucleotidephosphateoxidase4尼克酰胺腺嘌呤二核苷酸磷酸氧化酶4SIRT3silentinformationregulator3沉默信息调节因子2相关酶3FNFibronectin纤维连接蛋白α-SMAα-SmoothMuscleActinα-平滑肌肌动蛋白TGF-β1TransformingGrowthFactor-β1转化生长因子-β1Smad2Smad2SmaandMadhomologue丝/苏氨酸激酶受体p-MYPT1Myosinphosphatasetargetsubunit1肌球蛋白磷酸酶靶标亚基1WBWestern-blot蛋白质免疫印迹法目录摘要……………………………………………………………………………………1ABSTRACT……………………………………………………………………………3前言……………………………………………………………………………………5内容与方法……………………………………………………………………………81.两色金鸡菊黄酮纯化物对高糖软脂酸诱导HBZY-1细胞能量代谢紊乱的调控作用研究……………………………………………………………………81.1实验材料…………………………………………………………………81.2实验方法…………………………………………………………………111.3实验结果…………………………………………………………………161.4讨论………………………………………………………………………232.马里苷通过AMPK通路抑制高糖软脂酸诱导大鼠肾小球系膜细胞氧化应激及炎症损伤的作用机制……………………………………………………………………………242.1实验材料……………………………………………………………………242.2实验方法……………………………………………………………………272.3实验结果……………………………………………………………………292.4讨论…………………………………………………………………………38小结………………………………………………………………………………………42致谢………………………………………………………………………………………43参考文献………………………………………………………………………………44综述……………………………………………………………………………………51攻读硕士学位期间发表的学位论文…………………………………………………61导师评阅表………………………………………………………………………………62新疆医科大学硕士学位论文