【《去泛素化简概文献综述》2400字】

去泛素化简概文献综述泛素化是一个可逆的反应，可通过去泛素化酶（deubiquitylatingenzymes-DUB）将底物蛋白上的泛素去掉,这一过程称为去泛素化。目前发现的有100多种去泛素化酶，根据它们的域结构，DUBs可以分为五类：泛素c-端水解酶（theubiquitincarboxy-terminalhydrolases-UCHs),泛素特异性蛋白酶（theubiquitin-specificproteases-USPs),卵巢癌蛋白酶（theovariantumour-relatedproteases-OTUs),含有Machado-Joshphin区域的蛋白酶（theMachado–Josephdiseaseproteindomainproteases-MJDs)andtheJAB1/PAB1/MPN-domain-containingmetallo-enzymes(JAMMs)ADDINEN.CITEADDINEN.CITE.DATA(Nijmanetal.,2005)。JAMM家族是锌金属蛋白酶，而另外四种是半胱氨酸蛋白酶。去泛素化参与到多种生命活动中，例如基因转录，蛋白质降解，细胞周期等，同时也参与到免疫系统的调控中。UCH家族由少量结构相关的DUB组成，能够切开泛素化短肽，并在泛素内循环中有着重要作用。其中第一个被发现的是UCH-L1,与神经退行性疾病的发展有关ADDINEN.CITE<EndNote><Cite><Author>Gong</Author><Year>2007</Year><RecNum>180</RecNum><DisplayText>(GongandLeznik,2007)</DisplayText><record><rec-number>180</rec-number><foreign-keys><keyapp="EN"db-id="xd0z92r055rxd8epe2cvr2tfrzeat929etz0"timestamp="1597151342">180</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Gong,B.</author><author>Leznik,E.</author></authors></contributors><auth-address>TaubInstituteforResearchonAlzheimer'sdiseaseandtheAgingBrain,DepartmentofPathology,ColumbiaUniversity,NewYork,NewYork,USA.bg2058@</auth-address><titles><title>TheroleofubiquitinC-terminalhydrolaseL1inneurodegenerativedisorders</title><secondary-title>DrugNewsPerspect</secondary-title></titles><periodical><full-title>DrugNewsPerspect</full-title></periodical><pages>365-70</pages><volume>20</volume><number>6</number><edition>2007/10/11</edition><keywords><keyword>AlzheimerDisease/drugtherapy/*genetics/physiopathology</keyword><keyword>DrugDeliverySystems</keyword><keyword>Humans</keyword><keyword>HuntingtonDisease/drugtherapy/*genetics/physiopathology</keyword><keyword>Mutation</keyword><keyword>ParkinsonDisease/*genetics/physiopathology</keyword><keyword>ProteasomeEndopeptidaseComplex/metabolism</keyword><keyword>UbiquitinThiolesterase/genetics/*metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>0214-0934(Print) 0214-0934(Linking)</isbn><accession-num>17925890</accession-num><urls><related-urls><url>/pubmed/17925890</url></related-urls></urls><electronic-resource-num>10.1358/dnp.200138160</electronic-resource-num></record></Cite></EndNote>(GongandLeznik,2007)。USP家族是DUB中最大的家族，不同的生物中其种类和数量也是有差异的，人类基因组发现了53个USP家族基因。USP家族的特点是含有两个保守结构，一个是由19个氨基酸组成的cysteineboxes，另一个是由60-90个氨基酸组成的Histidineboxes，致使USP家族酶的作用原理都类似。USP对于K63,K48等多个位点的泛素链有水解能力，参与到多种信号通路和免疫调节中ADDINEN.CITEADDINEN.CITE.DATA(Nijmanetal.,2005)。OTU家族是DUB的第二大家族，第一个OUT基因是发现在果蝇中，具有调节卵巢发育的作用ADDINEN.CITEADDINEN.CITE.DATA(Makarovaetal.,2000)。OUT家族的去泛素化酶对泛素链的识别是有特异性的，如A20只选择含有K48位点的泛素链，而Cezanne则只识别K11位点的泛素链。研究证明多个OUT家族的DUB对免疫调节也有着重要作用。MJD和JAMM家族的DUB的研究较少，是否参与到免疫系统的调控尚不明确，因此在这就不做过多介绍。CYLD（Cylindromatosis，头帕肿瘤综合征蛋白）是USP家族的一种去泛素化酶，最早被鉴定为一种肿瘤抑制因子，因为CYLD的突变会导致毛囊肿瘤（cylindromatosis）ADDINEN.CITE<EndNote><Cite><Author>Biggs</Author><Year>1995</Year><RecNum>182</RecNum><DisplayText>(Biggsetal.,1995)</DisplayText><record><rec-number>182</rec-number><foreign-keys><keyapp="EN"db-id="xd0z92r055rxd8epe2cvr2tfrzeat929etz0"timestamp="1597153430">182</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Biggs,P.J.</author><author>Wooster,R.</author><author>Ford,D.</author><author>Chapman,P.</author><author>Mangion,J.</author><author>Quirk,Y.</author><author>Easton,D.F.</author><author>Burn,J.</author><author>Stratton,M.R.</author></authors></contributors><auth-address>SectionofMolecularCarcinogenesis,InstituteofCancerResearch,HaddowLaboratories,Belmont,Sutton,Surrey,UK.</auth-address><titles><title>Familialcylindromatosis(turbantumoursyndrome)genelocalisedtochromosome16q12-q13:evidenceforitsroleasatumoursuppressorgene</title><secondary-title>NatGenet</secondary-title></titles><periodical><full-title>NatGenet</full-title></periodical><pages>441-3</pages><volume>11</volume><number>4</number><edition>1995/12/01</edition><keywords><keyword>Carcinoma,AdenoidCystic/*genetics</keyword><keyword>*ChromosomeMapping</keyword><keyword>*Chromosomes,Human,Pair16</keyword><keyword>Female</keyword><keyword>Genes,Neoplasm</keyword><keyword>*Genes,TumorSuppressor</keyword><keyword>Haplotypes</keyword><keyword>Humans</keyword><keyword>LodScore</keyword><keyword>Male</keyword><keyword>MicrosatelliteRepeats</keyword><keyword>Pedigree</keyword><keyword>SkinNeoplasms/*genetics</keyword></keywords><dates><year>1995</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1061-4036(Print) 1061-4036(Linking)</isbn><accession-num>7493027</accession-num><urls><related-urls><url>/pubmed/7493027</url></related-urls></urls><electronic-resource-num>10.1038/ng1295-441</electronic-resource-num></record></Cite></EndNote>(Biggsetal.,1995)。CYLD主要包含两个重要结构域：一个是包含三个细胞骨架和细胞运动相关的结构域cytoskeletal-associatedprotein-glycine-conserved（CAP-Gly），另一个是包含zinc-finger-likeB-box的泛素水解结构域（ubiquitincarboxy-terminalhydrolases-UCHorUSP）。USP结构域主要介导CYLD的去泛素化酶活性，同时也是小鼠生长发育所必须的ADDINEN.CITEADDINEN.CITE.DATA(Kovalenkoetal.,2003;Trompoukietal.,2003;Trompoukietal.,2009)。CAP-Gly结构域能够与微管蛋白相互作用并促进微管的组装和使微管更加稳定。同时CAP-Gly结构域影响微管的polymerization-depolymerization，从而影响细胞的迁移ADDINEN.CITEADDINEN.CITE.DATA(Gaoetal.,2008;SteinmetzandAkhmanova,2008)。此外，CYLD能与组蛋白去乙酰化酶6（HDAC6）相互作用，调节微管蛋白的乙酰化修饰，进而调节微管蛋白的组装ADDINEN.CITEADDINEN.CITE.DATA(Wickstrometal.,2010)。CAP-Gly结构域还能够识别和结合IkB激酶IKKγ调节NF-kB信号通路ADDINEN.CITEADDINEN.CITE.DATA(Saitoetal.,2004)。第一条发现被CYLD所调控的信号通路是NF-κB信号通路。NF-κB信号通路能够调节多种细胞生物学功能，例如细胞的分化，凋亡和增殖等。当细胞受到肿瘤坏死因子（tumornecrosisfactor-alpha-TNF-a）或LPS等其他信号刺激时，TRAF家族成员能对多种下游信号通路中的分子和自身泛素化，从而招募并激活TAK，活化的TAK能够磷酸化IKK复合体，同时对IKKγ（NEMO）进行K63位泛素化修饰，进而激活IKKβ，活化的IKKβ能够磷酸化IkB，从而被K48泛素化修饰并降解，释放P50和P65进入细胞核调控多种基因的转录。研究表明CYLD能够与TRAF家族相互作用并负调控NF-κB信号通路，导致细胞凋亡ADDINEN.CITEADDINEN.CITE.DATA(Brummelkampetal.,2003;Kovalenkoetal.,2003;Trompoukietal.,2003)。另一方面CYLD能够去泛素化receptor-interactingprotein1(RIP1)而调控NF-κB信号通路,进而影响精子的凋亡ADDINEN.CITE<EndNote><Cite><Author>Wright</Author><Year>2007</Year><RecNum>191</RecNum><DisplayText>(Wrightetal.,2007)</DisplayText><record><rec-number>191</rec-number><foreign-keys><keyapp="EN"db-id="xd0z92r055rxd8epe2cvr2tfrzeat929etz0"timestamp="1597217367">191</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wright,A.</author><author>Reiley,W.W.</author><author>Chang,M.</author><author>Jin,W.</author><author>Lee,A.J.</author><author>Zhang,M.</author><author>Sun,S.C.</author></authors></contributors><auth-address>DepartmentofMicrobiologyandImmunology,PennsylvaniaStateUniversityCollegeofMedicine,500UniversityDrive,Hershey,PA17033,USA.</auth-address><titles><title>RegulationofearlywaveofgermcellapoptosisandspermatogenesisbydeubiquitinatingenzymeCYLD</title><secondary-title>DevCell</secondary-title></titles><periodical><full-title>DevCell</full-title></periodical><pages>705-16</pages><volume>13</volume><number>5</number><edition>2007/11/06</edition><keywords><keyword>Animals</keyword><keyword>*Apoptosis</keyword><keyword>CysteineEndopeptidases/genetics/*physiology</keyword><keyword>GTPase-ActivatingProteins/metabolism</keyword><keyword>GermCells/*physiology</keyword><keyword>Mice</keyword><keyword>Mice,Knockout</keyword><keyword>NF-kappaB/metabolism</keyword><keyword>Phosphorylation</keyword><keyword>SignalTransduction</keyword><keyword>*Spermatogenesis</keyword><keyword>Ubiquitination</keyword></keywords><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1534-5807(Print) 1534-5807(Linking)</isbn><accession-num>17981138</accession-num><urls><related-urls><url>/pubmed/17981138</url></related-urls></urls><electronic-resource-num>10.1016/j.devcel.2007.09.007</electronic-resource-num></record></Cite></EndNote>(Wrightetal.,2007)。CYLD缺失的T细胞中，TAK1激酶显示被过度激活而导致NF-κB信号通路过度活化，因此CYLD能够抑制TAK1的泛素化和激活ADDINEN.CITEADDINEN.CITE.DATA(Reileyetal.,2007)。此外，在紫外线的刺激下，B淋巴细胞瘤蛋白3（BCL3）能够被泛素化并进入细胞核与P50和P52相互作用从而调控基因的转录。CYLD能够去泛素化BCL3并阻止BCL3的入核，抑制NF-κB信号通路ADDINEN.CITEADDINEN.CITE.DATA(Massoumietal.,2006;Parketal.,2006)。此外CYLD还能通过影响TRAF家族的泛素化而影响下游除了NF-κB信号通路的c-JunN-terminalkinase(JNK)信号通路。Zhang等人发现CYLD敲除的巨噬细胞显示TRAF2泛素化的升高和JNK的过度活化ADDINEN.CITE<EndNote><Cite><Author>Zhang</Author><Year>2005</Year><RecNum>32</RecNum><DisplayText>(Zhangetal.,2005)</DisplayText><record><rec-number>32</rec-number><foreign-keys><keyapp="EN"db-id="xd0z92r055rxd8epe2cvr2tfrzeat929etz0"timestamp="1596118585">32</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zhang,M.</author><author>Windheim,M.</author><author>Roe,S.M.</author><author>Peggie,M.</author><author>Cohen,P.</author><author>Prodromou,C.</author><author>Pearl,L.H.</author></authors></contributors><auth-address>SectionofStructuralBiology,InstituteofCancerResearch,ChesterBeattyLaboratories,237FulhamRoad,LondonSW36JB,UnitedKingdom.</auth-address><titles><title>Chaperonedubiquitylation--crystalstructuresoftheCHIPUboxE3ubiquitinligaseandaCHIP-Ubc13-Uev1acomplex</title><secondary-title>MolCell</secondary-title></titles><periodical><full-title>MolCell</full-title></periodical><pages>525-38</pages><volume>20</volume><number>4</number><edition>2005/11/26</edition><keywords><keyword>Animals</keyword><keyword>CellLine</keyword><keyword>Crystallography,X-Ray</keyword><keyword>Dimerization</keyword><keyword>HSP90Heat-ShockProteins/metabolism</keyword><keyword>Humans</keyword><keyword>Lysine/metabolism</keyword><keyword>Mice</keyword><keyword>Polyubiquitin/metabolism</keyword><keyword>ProteinStructure,Tertiary</keyword><keyword>TranscriptionFactors/*chemistry/metabolism</keyword><keyword>Ubiquitin-ConjugatingEnzymes/*chemistry/metabolism</keyword><keyword>Ubiquitin-ProteinLigases/*chemistry/metabolism</keyword></keywords><dates><year>2005</year><pub-dates><date>Nov23</date></pub-dates></dates><isbn>1097-2765(Print) 1097-2765(Linking)</isbn><accession-num>16307917</accession-num><urls><related-urls><url>/pubmed/16307917</url></related-urls></urls><electronic-resource-num>10.1016/j.molcel.2005.09.023</electronic-resource-num></record></Cite></EndNote>(Zhangetal.,2005)。CYLD还能与视磺酸诱导基因（RIG-1）相结合并调控RIG-1的泛素化，影响干扰素的产生ADDINEN.CITEADDINEN.CITE.DATA(Friedmanetal.,2008)。在T细胞分化方面，CYLD的缺失导致小鼠脾脏CD4+和CD8+T细胞数量明显减少。其原因可能是CYLD的缺失导致LCK持续的被泛素化和降解，而致使T细胞不能够被激活。另一方面可能是因为TAK的磷酸化过度激活ADDINEN.CITEADDINEN.CITE.DATA(Reileyetal.,2007;Reileyetal.,2006)。细胞周期主要包含四个周期：合成前期（G1），合成期（S），合成后期（G2）和分裂期（M）。分裂期又可分为有丝分裂和胞质分裂。在黑色素瘤细胞和角质形成细胞中过表达CYLD后发现，细胞G1到S期的转换延迟。此外，CYLD缺失的HeLa细胞表现出细胞分裂期的明显延迟。进而的研究发现，CYLD能够与调控细胞周期的PLK1结合并去其泛素化，影响中心体的成熟和纺锤体的组装，抑制胞质分裂ADDINEN.CITE<EndNote><Cite><Author>Stegmeier</Author><Year>2007</Year><RecNum>199</RecNum><DisplayText>(Stegmeieretal.,2007)</DisplayText><record><rec-number>199</rec-number><foreign-keys><keyapp="EN"db-id="xd0z92r055rxd8epe2cvr2tfrzeat929etz0"timestamp="1597219346">199</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Stegmeier,F.</author><author>Sowa,M.E.</author><author>Nalepa,G.</author><author>Gygi,S.P.</author><author>Harper,J.W.</author><author>Elledge,S.J.</author></authors></contributors><auth-address>DepartmentofGenetics,HarvardMedicalSchool,CenterforGeneticsandGenomics,HowardHughesMedicalInstitute,BrighamandWomen'sHospital,Boston,MA02115,USA.</auth-address><titles><title>ThetumorsuppressorCYLDregulatesentryintomitosis</title><secondary-title>ProcNatlAcadSciUSA</secondary-title></titles><periodical><full-title>ProcNatlAcadSciUSA</full-title></periodical><pages>8869-74</pages><volume>104</volume><number>21</number><edition>2007/05/15</edition><keywords><keyword>AminoAcidSequence</keyword><keyword>CellLine</keyword><keyword>DeubiquitinatingEnzymeCYLD</keyword><keyword>GeneExpressionRegulation</keyword><keyword>Humans</keyword><keyword>*Mitosis</keyword><keyword>MolecularSequenceData</keyword><keyword>NF-kappaB/metabolism</keyword><keyword>ProteinBinding</keyword><keyword>SignalTransduction</keyword><keyword>TumorSuppressorProteins/genetics/*metabolism</keyword><keyword>ets-DomainProteinElk-1/chemistry/genetics/metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>May22</date></pub-dates></dates><isbn>0027-8424(Print) 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