自噬与泛素化蛋白降解途径的分子机制及其功能

HEREDITAS(Beijing)20121,34(1):5―18ISSN0253-9772综述收稿日期:2011−06−03;修回日期:2011−08−19基金项目:(2009ZX08009-148B)作者简介:,,E-mail:[e-mail]通讯作者:,,,E-mail:[e-mail]网络出版时间:2011-8-2411:11:40URL::10.3724/SP.J.1005.2012.00005自噬与泛素化蛋白降解途径的分子机制及其功能陈科,程汉华,周荣家,430072细胞内所有的蛋白质和大多数的细胞外蛋白都在不断的进行更新,即它们在不断地被降解,并被新合成的蛋白质取代。细胞内蛋白的降解主要通过两个途径,即自噬和泛素蛋白酶体系统。自噬是一种由溶酶体介导的细胞内过多或异常蛋白质的降解机制。在细胞内主要有3种类型的自噬,即分子伴侣介导的自噬、微自噬和巨自噬。泛素蛋白酶体系统是由泛素介导的一种高度复杂的蛋白降解机制,它参与降解细胞内许多蛋白质并且这个过程具有高度特异性。细胞内蛋白质的降解参与调节许多细胞过程,包括细胞周期、DNA修复、细胞生长和分化、细胞质量的控制、病原生物的感染反应和细胞凋亡等。许多严重的人类疾病被认为是由于蛋白质降解系统的紊乱而引起的。文章综述了自噬和泛素化途径及其分子机制,以及蛋白质降解系统紊乱的病理学意义。蛋白质降解;自噬;泛素蛋白酶体系统Molecularmechanismsandfunctionsofautophagyandtheubiq-uitin-proteasomepathwayCHENKe,CHENGHan-Hua,ZHOURong-JiaLifeScienceCollege,WuhanUniversity,Wuhan430072,ChinaAbstract:Allproteinsineukaryoticcellsarecontinuallybeingdegradedandreplaced.Autophagyandtheubiq-uitin-proteasomesystemaretwomechanismsforintracellularproteindegradation.Autophagyismediatedbylysosome,andisfurtherdividedintochaperone-mediatedautophagy,microautophagyandmacroautophagy.Theubiquitin-proteasomesystemishighlycomplexandmediatedbyubiquitin,whichparticipatesinintracellularproteindegradationinaspecificmanner.Itisnowknownthatdegradationofintracellularproteinsisinvolvedinregulationofaseriesofcellularprocesses,includingcell-cycledivision,DNArepair,cellgrowthanddifferentiation,qualitycontrol,pathogeninfection,andapoptosis.Theaberrationsintheproteindegradationsystemsareinvolvedinmanyserioushumandiseases.Thepresentreviewsum-marizesthemechanismsofproteindegradationandrelatedhumandiseases.Keywords:proteindegradation;autophagy;ubiquitin-proteasomesystem,,6HEREDITAS(Beijing)201234,,,,,,[1],[2],,(Autophagy)(Ubiquitin-protea-somesystem,UPS),,,UPS,,1,,(1A)[2]3,(Macroautophagy)(Microautophagy),/,[3],,HSC70,,[3]图1真核生物细胞内蛋白质降解的两种降解系统[2]1:7,,,,,,,,[4,5],,,,[6]1.1,,(Auto-phagy-relatedgenes,ATG)atg(Autophagosomes)(2)Atg1/ULK1(Atg1ULK1),ATG1ATG13ATG173[7,8],1(Mammaliantargetofrapamycincomplex1,mTORC1)Atg1/ULK1mTORC1,5,Raptor(ULK1)mTOR(/)mTORC1Atg1/ULK1ATG13,mTORC1Atg1/ULK1,(Nucleation)(Elongation)[8]ATG6(Beclin1),3VPS34(3)3(Phosphatidylinositol-3-phosphate,PI3P)[9](ATG12ATG8/LC3)E1ATG7E2ATG10ATG12ATG5,Atg16L1(Pre-autophagosomalstructures,PAS)ATG8/LC3ATG4,(Phospha-tidylethanolamine,PE)E1ATG7E2图2真核生物细胞内自噬的过程[9]8HEREDITAS(Beijing)201234ATG3ATG8/LC3LC3(LC3-I)(LC3-II),LC3-IILC3-II,,[8,10]ATG9,[9],(Autolysosomes),,,[8,10]1.2,,[11],,,,(Mitophagy)(Ribophagy)(Reticulopha-gy)(Pexophagy)(Lipophagy)[8],,,,,,p62LC3[12],Atg32Atg8/LC3Atg11,[13],,Pink-1E3Parkin,VDAC1K27,VDAC1p62[14]1.3,,mTORC1mTORC1,ULK1mTORC1,TSCTSC2TSC1GTP(GTPase-activatingprotein,GAP),Rheb,mTORC1[15]mTORC1PI3K-PKBPKBTSC2TSC,mTORC1[16],PTENPI3K-PKB[17]LKB1-AMPKmTORC1LKB1-AMPK“”,AMP/ATPAMPKTSC2mTORC1,[18]LKB1-AMPKp27,p27,p27,[19],AMPKULK1,[20.21]mTORC1“”HIFREDD1,REDD1TSCmTORC1,[22],HIF[23],p531:9,p53AMPKmTORC1[24],p53DRAM[25]p53sestrin1sestrin2AMPKmTORC1[26],p53[27],(Insulin)(1)mTORAtg1/ULK1;(2)InsulinPKB/AktFoxO3,FoxO3[28]mTOR,—(Ammonia)TNF–α[8],(Glucagon)[8]1.4,,,,,,,1.4.1自噬与蛋白质聚集类疾病,(1);(2);(3)/,,,,,[29],α-1-(AT)ATAT,AT[30],,,(HD)(AD)[31],[31],[32],,[29],,,,,1.4.2自噬与肌病和溶酶体贮积症,,,,Danon,,[29]LAMP-2b,10HEREDITAS(Beijing)201234[33](Pompe)Danon,,α-α-,Beclin1ATG12ATG8[34][31]1.4.3自噬与肿瘤的发生,,,,Beclin1MAP1LC3ATG7[33],PI3K-PKBmTOR[12],,,[35],,[35,36],,,p53DRAM,[25],,ATG5[37],p62,[12]p62p62[38]p62,p62,,DNA,p62p62p62[12],,,mTOR[39],,,HeLa[40],,1.4.4自噬与致病菌和病毒感染,,,,,[41]DNARNA,(IFN),IFNIFN[42],,ICP34.5PKR[43]RNA,1:11[44]2泛素蛋白酶体系2070[45],,,,[46],,[47],,,,UPS[48]UPS,[49]—,10~2026S,20S19S20S,,2(7a)2(7β)(1B)[2],20S,,220S1A,19S20S,26S,26S11SPA28REG,26SATP[2]2.176,,3(1),ATP,CE1,E1;(2)E1E2;(3)E3E2E1E2E3,26S20Sβ,,26S,(3),UPSE150E2,E2E3,E31000,图326S蛋白酶体降解泛素化蛋白底物的示意图2.2,-12HEREDITAS(Beijing)201234,,,2.2.1蛋白质的加工,,,,,,NF-kappaBSpt23pMga2p[50]2.2.2细胞周期的调控(CDK),CDK(Cyclin),,Cyclin-CDK,Cyclin-,,,CyclinB,,CyclinAE3-(APC),APC,ME3,M,[51],ChfrChfrE3,HDAC1Plk1Kif22HLTF,Chfr,,ChfrPLK1,Cdc2,,,[52~55],Chfr,Plk1,2.2.3细胞凋亡,,[56,57],,,,,,,,[57]2.2.4DNA修复p53,“”50%p53,p53,,MDM2E3p53p53DNA,p53MDM2,,p53p53,,DNAp53,,DNA[58]2.2.5细胞应激反应,,,,Hsp27Hsp90-,Hsp2726S,Hsp27,,I-κBαI-κBαNF-κB,,-I-κBα,NF-κB[59],Hsp70,E3(CHIP)1:13,[59],,,PARP2.2.6调节免疫反应,,,(MHC)I,,,,T[60],,MHC11Sβ(β1iβ2iβ5i,),γ[61]NF-κB,26SNF-κB,NF-κB,NF-κBI-κBp105NF-κBp50,2.2.7调节生长和发育,,,[62],(Auxin)(Phytohormone),(Aux/IAA)SCFTIR1SCFAux/IAA,Auxin(ARF),ARF[63]ARFARFAux/IAAARF[60],,,,,,,NEDD4IGF-1,(IGF)3(IGF-1IGF-2)(IGF-1RIR)IGF-1IGF-2,IGF-1,IGF-1R,IGF-1NEDD4E3,PTENNEDD4IGF1R,NEDD4Grb10,,IGF1RGrb10IGF-1RIR,NEDD4IGF-1RNEDD4[64]2.3,,,UPS2UPS();()[47],[65]1UPSUPS,UPS2.3.1VHL相关肿瘤VHLE3,(HIF)αHIFDNA,14HEREDITAS(Beijing)201234表1由UPS异常导致的人类疾病(Angelmansyndrome,AS)E3E6-AP[47](AR-JP)E3parkin[47]LiddleUPSβ/γ[47]VHLE3VHL[47]UPSβ-catenin[47]UPSFANCD2[47]HPVp53[47]E3HDM2SKP2UPS[47]E3BRCA1[47]CYLD[47]UPSMYBPC3[66]UPS[67](SCZ)(BPD)UPS[68]CFTR[69]E3MURF-1atrogin-1[70]100~200,HIFα3HIF1αHIF2αHIF3αHIF1αHIF2α2,HIF3α[71]VHL,VHLE3HIFα,[71],VHL-/-