Investigator,NIBS,Beijing,ChinaPhone：010-80726688-8560
Fax：010-80728046
E-mail：shaofeng@nibs.ac.cn
教育经历Education1996年北京大学技术物理系应用化学专业学士
B.S.AppliedChemistry,PekingUniversity,Beijing,China
1999年中国科学院生物物理所分子生物学硕士
M.S.MolecularBiology,InstituteofBiophysics,ChineseAcademyofSciences,Beijing,China
2003年美国密西根大学医学院生物化学博士
Ph.D.BiologicalChemistry,UniversityofMichiganMedicalSchool,AnnArbor,MI,USA
工作经历ProfessionalExperience2012-present北京生命科学研究所资深研究员
Investigator,NationalInstituteofBiologicalSciences,Beijing,China
2009-2012年北京生命科学研究所高级研究员
AssociateInvestigator,NationalInstituteofBiologicalSciences,Beijing,China
2005-2009年北京生命科学研究所研究员
AssistantInvestigator,NationalInstituteofBiologicalSciences,Beijing,China
2004-2005年哈佛大学医学院博士后
DamonRunyonPostdoctoralResearchFellow,HarvardMedicalSchool,Boston,USA
2003-2004年美国加洲大学圣地亚哥分校医学院博士后
PostdoctoralResearchFellow,SchoolofMedicine,UniversityofCalifornia,SanDiego,USA
研究概述ResearchDescription我们实验室的研究兴趣集中在病原细菌感染宿主和宿主先天性免疫防御的分子机制。对于细菌感染来说，通过特殊的分泌系统向宿主细胞中注入毒素效应蛋白是病原细菌普遍采用的重要致病机制。这些效应蛋白往往以非常有效的方式作用于宿主信号转导中的关键分子，使其发生功能紊乱。效应蛋白的作用有利于细菌在宿主中的生存和进一步感染。我们的研究以多种临床上常见的病原菌（Shigella,Salmonella,EnteropathogenicE.coli,Legionella以及Burkholderia）为模式，着眼于发现并揭示效应蛋白在抑制真核细胞重要信号转导通路中的一些新的、较为普遍的生物化学机制。实验室最近的研究工作在这方面取得了一系列的突破和发现。1)来源于Shigella，Salmonella和植物假单胞杆菌的OspF家族三型分泌系统效应蛋白通过一种崭新的磷酸化苏氨酸裂合酶的活性，特异性地、不可逆地“去磷酸化”宿主MAPK激酶并使其失活,从而抑制宿主细胞因子的表达。2)Legionella的四型分泌系统效应蛋白LegK1能模拟宿主中的IKK激酶而磷酸化IκBa蛋白，并诱导其被泛素化和降解，进而激活NF-κB通路并对巨噬细胞凋亡产生抑制作用。3)三型分泌系统效应蛋白CHBP（Burkholderia）和Cif（EnteropathogenicE.coli）特异性地修饰（脱氨）泛素和泛素样蛋白NEDD8中Gln-40。这种修饰能有效地阻断宿主泛素-蛋白酶体通路并导致诸如细胞周期等重要细胞生理过程发生功能紊乱。我们认为，这些研究不仅对理解感染和致病的分子机理有极大的促进作用，更为重要的是，由于病原细菌和宿主(人类)长期共同进化，其分泌的毒素效应蛋白也为我们研究真核细胞本身的信号转导机制提供了独特的、前所未有的视角和研究工具。同时，我们也对宿主巨噬细胞如何通过其先天性免疫系统来拮抗病原微生物感染的机制感兴趣。在受到感染后，巨噬细胞能感受到多种来自病原菌或其它病原微生物的一些模式分子，从而激活一类被称为炎症小体的蛋白复合物，同时发生炎症性细胞坏死和分泌白介素1b。炎症小体利用一类叫作NOD-like的受体分子感受来自病原菌的信号，但除此之外人们对炎症小体的组装和其上游的信号转导机制了解甚少。我们将结合生物化学、细胞生物学以及小鼠遗传学等多种手段来研究和阐明炎症小体被激活的生化机制。Dr.FengShao’slaboratoryisinterestedinstudyingmolecularmechanismsofbacterialinfectionandhostinnateimmunitydefense.BacterialpathogensusespecializedsecretionsystemssuchastypeIII/IVsecretionsystemtoinjecteffectorproteinsintohostcells,servingasakeyanduniversalvirulencemechanism.Theeffectorsusuallyharborauniqueandpotentactivitythatmodulatesthefunctionofkeysignalingmoleculesinthehost,andthisplaysacriticalroleinbacterialsurvivalandsystemicinfections.UsingpathogenssuchasShigella,Salmonella,EnteropathogenicE.coli(EPEC),LegionellaandBurkholderiaasthemodel,weareworkingtodiscoverandrevealsomenovelandcommonbiochemicalmechanismsutilizedbybacterialeffectorsinmodulatinghostsignaltransductionpathways.Ourrecentworkhasledtoseveralinterestingdiscoveries.1)TheOspFfamilyoftypeIIIeffectors,conservedinShigella,SalmonellaandtheplantpathogenP.syringae,harborsanovelphosphothreoninelyaseactivitythatspecificallyandirreversibly“dephosphorylates”hostMAPKs,leadingtokinaseinactivationandinhibitedcytokineproduction.2)TheLegionellatypeIVeffectorLegK1mimicshostIKKtophosphorylateIkBa,whichresultsinubiquitinationanddegradationofIkBaandconsequentactivationofhostanti-apoptoticNF-kBsignaling.3)TypeIIIeffectorsCHBP(Burkholderia)andCif(EPEC)useapapain-likecatalyticactivitytodeamidateubiquitinandubiquitin-likeproteinNEDD8.Thisleadstodysfunctioningofhostubiquitin-proteasomesystem,andthereforemanyimportantcellularprocessessuchascellcycleprogressionbecomeabnormal.Webelievethatsuchkindofresearchanddiscoveryisnotonlyrevealinginbacterialpathogenesis,butalsoprovidesanunprecedenteduniqueangleforstudyingthemechanismofeukaryoticsignaltransduction.Meanwhile,wearealsointerestedinhowthehostusesitsinnateimmunitysystemtocounteractbacterialinfection,particularlytheinflammasomepathwayinmacrophages.Macrophagesensesmanykindsofpathogen-derivedmolecularpatternsandtherebyactivatesthecytoplasmicinflammasomecomplex,andthisleadstoIl-1bproductionandinflammatorycelldeathofthemacrophage.TheNOD-likereceptorininflammasomeisrequiredforsensingbacteria-derivedsignals.However,littleisknownabouthowtheinflammasomeisassembled/activated,andthesignalingcascadeupstreamoftheinflammasomeremainsobscure.Wearecombiningmultipleapproachesincludingbiochemicalreconstitution,cellbiologyandmousegeneticstoidentifynewcomponentsinpathogen-inducedinflammasomeactivationandtofurtherrevealtheunderlyingbiochemicalmechanism.发表文章PublicationsResearcharticles:1.DongN,ZhuY,LuQ,HuL,ZhengY,ShaoF.(2012)StructurallyDistinctBacterialTBC-likeGAPsLinkArfGTPasetoRab1InactivationtoCounteractHostDefenses.Cell,150,1029-41.2.GeJ,GongYN,XuY,ShaoF.(2012)PreventingbacterialDNAreleaseandabsentinmelanoma2inflammasomeactivationbyaLegionellaeffectorfunctioninginmembranetrafficking.Proc.Natl.Acad.Sci.,109,6193-8.3.ZhangL,DingX,CuiJ,XuH,ChenJ,GongYN,HuL,ZhouY,GeJ,LuQ,LiuL,ChenS,ShaoF.(2012)Cysteinemethylationdisruptsubiquitin-chainsensinginNF-kBactivation.Nature,481,204-8.4.ZhaoY,YangJ,ShiJ,GongYN,LuQ,XuH,LiuL,ShaoF.(2011)TheNLRC4inflammasomereceptorsforbacterialflagellinandtypeIIIsecretionapparatus.Nature,477,596–600.5.CuiJ,YaoQ,LiS,DingX,LuQ,MaoH,LiuL,ZhengN,ChenS,ShaoF.(2010)Glutaminedeamidationanddysfunctionofubiquitin/NEDD8inducedbyabacterialeffectorfamily.Science,329,1215-8.6.GongYN,WangX,WangJ,YangZ,LiS,YangJ,LiuL,LeiX,ShaoF.(2010)Chemicalprobingrevealsinsightsintothesignalingmechanismofinflammasomeactivation.CellResearch,20,1289-305.7.DongN,LiuL,ShaoF.(2010)AbacterialeffectortargetshostDH-PHdomainRhoGEFsandantagonizesmacrophagephagocytosis.EMBOJ.,29,1363-76.8.ZhuY,HuL,ZhouY,YaoQ,LiuL,ShaoF.(2010)StructuralmechanismofhostRab1activationbythebifunctionalLegionellatypeIVeffectorSidM/DrrA.Proc.Natl.Acad.Sci.,107,4699-704.9.GeJ,XuH,LiT,ZhouY,ZhangZ,LiS,LiuL,ShaoF.(2009)ALegionellatypeIVeffectoractivatestheNF-κBpathwaybyphosphorylatingtheIκBfamilyofinhibitors.Proc.Natl.Acad.Sci.,106,13725-30.10.ChenY,YangZ,MengM,ZhaoY,DongN,YanH,LiuL,DingM,Peng,HB,ShaoF.(2009)CullinmediatesdegradationofRhoAthroughevolutionarilyconservedBTBadaptorstocontrolactincytoskeletonstructureandcellmovement.Mol.Cell,35,841-55.11.YaoQ,CuiJ,ZhuY,WangG,HuL,LongC,Cao,R,LiuX,HuangN,ChenS,LiuL,ShaoF.(2009)AbacterialtypeIIIeffectorfamilyusesthepapain-likehydrolyticactivitytoarrestthehostcellcycle.Proc.Natl.Acad.Sci.,106,3716-21.12.ZhuY.,LiH.,HuL.,Wang,J.,ZhouY.,PangZ.,LiuL.,ShaoF.(2008)StructureofaShigellaeffectorrevealsanewclassofubiquitinligases.NatureStructural&MolecularBiology,15,1302-8.13.ZhuY,LiH,LongC,HuL,XuH,LiuL,ChenS,WangDC,ShaoF.(2007)StructuralinsightsintotheenzymaticmechanismofthepathogenicMAPKphosphothreoninelyase.Mol.Cell,28,899-913.14.ZhangJ,ShaoF,LiY,CuiH,ChenL,LiH,ZouY,LongC,LanL,ChaiJ,ChenS,TangX,ZhouJM.(2007)APseudomonassyringaeeffectorinactivatesMAPKstosuppressPAMP-inducedimmunity.CellHost&Microbe,1,175-85.15.LiH,XuH,ZhouY,ZhangJ,LongC,LiS,ChenS,ZhouJM,ShaoF.(2007)ThephosphothreoninelyaseactivityofabacterialtypeIIIeffectorfamily.Science,315,1000-3.16.AltoNM,ShaoF,LazarCS,BrostRL,ChuaG,Mattoo,SM,McMahonSA,GhoshP,HughesTR,BooneC,DixonJE.(2006)IdentificationofabacterialtypeIIIeffectorfamilywithG-proteinmimicryfunctions.Cell,124,133-45.17.ZhuM,ShaoF,InnesRW,DixonJE,XuZ.(2004)ThecrystalstructureofPseudomonasavirulenceproteinAvrPphB:apapain-likefoldwithadistinctsubstrate-bindingsite.Proc.Natl.Acad.Sci.,101,302-7.18.ShaoF,Golstein,C,AdeJ,StoutemyerM.,DixonJE,InnesRW.(2003)CleavageofArabidopsisPBS1byabacterialtypeIIIeffector.Science,301,1230-3.19.ShaoF,VacratsisPO,BaoZ,BowersKE,FierkeCA,DixonJE.(2003)BiochemicalcharacterizationoftheYersiniaYopTprotease:cleavagesiteandrecognitionelementsinRhoGTPases.Proc.Natl.Acad.Sci.,100,904-9.20.ShaoF,MerrittPM,BaoZ,InnesRW,DixonJE.(2002)AYersiniaeffectorandaPseudomonasavirulenceproteindefineafamilyofcysteineproteasesfunctioninginbacterialpathogenesis.Cell,109,575-88.21.ShaoF,BaderMW,JakobU,BardwellJC.(2000)DsbG,aproteindisulfideisomerasewithchaperoneactivity.J.Biol.Chem.,275,13349-52.22.ShaoF,HuZ,XiongYM,HuangQZ,WangCG,ZhuRH,WangDC.(1999)AnewantifungalpeptidefromtheseedsofPhytolaccaamericana:characterization,aminoacidsequenceandcDNAcloning.Biochim.Biophys.Acta,1430,262-8.23.ShaoF,XiongYM,ZhuRH,LingM,ChiCW,WangDC.(1999)ExpressionandpurificationoftheBmKM1neurotoxinfromthescorpionButhusmartensiiKarsch.ProteinExpr.Purif.,17,358-65.Invitedreviewarticles:24.ZhaoY,ShaoF.(2012)NLRC5:aNOD-likereceptorproteinwithmanyfacesinimmuneregulation.CellResearch,22,1099-101.25.GongYN,ShaoF.(2012)SensingbacterialinfectionsbyNAIPreceptorsinNLRC4inflammasomeactivation.Protein&Cell,3,98-105.26.GeJ,ShaoF.(2011)ManipulationofhostvesiculartraffickingandinnateimmunedefensebyLegionellaDot/Icmeffectors.Cell.Microbiol.,13,1870-80.27.CuiJ,ShaoF.(2011)Biochemistryandcellsignalingtaughtbybacterialeffectors.TrendsinBiochemicalSciences,36,532-40.28.ShaoF.(2008)BiochemicalfunctionsofYersiniatypeIIIeffectors.CurrentOpinioninMicrobiology,11,21-9.29.JurisSJ,ShaoF,DixonJE.(2002)Yersiniaeffectorstargetmammaliansignalingpathways.Cell.Microbiol.,4:201-11(Co-firstauthor).
