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. 2018 Feb 25;47(1):82–88. [Article in Chinese] doi: 10.3785/j.issn.1008-9292.2018.02.12

蛋白泛素化修饰调控炎性肠疾病发生和发展的研究进展

Protein ubiquitination on the regulation of inflammatory bowel disease

Jing LING 1, Hongrui LI 1, Weilin CHEN 1,2,*
PMCID: PMC10393695  PMID: 30146816

Abstract

炎性肠疾病是一种慢性胃肠道功能紊乱的炎症性疾病。泛素化是一类重要的蛋白质翻译后修饰方式。近年来关于泛素化-去泛素化系统在炎性肠疾病发生和发展中的作用已成为研究热点。目前蛋白泛素化修饰调控炎性肠疾病过程所需的E3泛素连接酶中，分子生物学研究较为清楚的有环指蛋白183（RNF183）、环指蛋白20（RNF20）、Itch和锌指蛋白A20。其中RNF183可靶向核因子κB抑制蛋白α（IκBα）泛素化降解促进NF-κB活化；RNF20促进组蛋白H2B单泛素化从而下调相关炎症因子的转录；Itch促进维甲酸核孤儿受体γt泛素化降解抑制IL-17介导的肠炎；A20以其特有的泛素化和去泛素化双重活性影响炎性肠疾病的发展。本文综述了以上分子在炎性肠疾病发生、发展和转归中的作用及调控机制。

炎性肠疾病(inflammatory bowel diseases，IBD)包括溃疡性结肠炎和克罗恩病，是一种胃肠道功能紊乱的慢性炎症性疾病 [ 1] 。IBD的发病机制尚不明确，目前认为主要是由遗传、感染、免疫、环境等多种因素相互作用所致 [ 2] 。肠道免疫系统处在一个精细调节的环境中，一方面对肠道致病微生物产生免疫，另一方面对食物和对人体有利的菌群产生耐受。一旦这种平衡被打破，即可促进慢性肠炎的发生 [ 3] 。Roy等 [ 4] 证实，肠道菌群通过介导固有免疫和适应性免疫应答来调节IBD的发展，因此肠道菌群不同可导致个体对IBD易感性的差异。近年来，随着工业化和城市化的发展，IBD在发展中国家的发病率上升，并逐渐成为一种全球性的疾病 [ 5] 。目前，IBD尚无有效的治疗方法。因此，明确IBD的病因和发病机制，寻找特异性的治疗方法越来越受到关注。

蛋白泛素化修饰能够调控多种信号介导的炎症反应，在炎症性疾病如IBD的发生、发展和转归中发挥着重要作用。泛素是一种由76个氨基酸组成的小分子蛋白质，广泛存在于真核细胞中，且序列高度保守 [ 6] 。泛素化是指泛素在一系列酶的催化作用下共价结合到靶蛋白的过程，其参与转录调节、DNA损伤修复、细胞周期、囊泡运输等生理过程，涉及生命活动的各方面 [ 7] 。泛素化过程通常需要E1泛素激活酶、E2泛素偶联酶和E3泛素连接酶的协同作用 [ 8- 10] 。与磷酸化相似，泛素化也是一个可逆的过程，主要由去泛素化酶介导 [ 6] 。

相关研究表明，泛素化修饰通过调控NF-κB信号通路，既可以作用于肠黏膜炎性损伤，也可影响肠上皮细胞的通透性和凋亡。迄今，已发现多种E3泛素连接酶参与调控IBD的进程 [ 2] 。如含有环指结构域(RING结构域)的三重基序蛋白31(tripartite motif containing 31, TRIM31)可促进核苷酸结合寡聚域样受体热蛋白结构域相关蛋白3(NOD-like receptor pyrin domain-containing protein 3, NLRP3) K48连接的多聚泛素化修饰从而进入蛋白酶体降解途径，而NLRP3炎性小体在维持肠道稳态和预防结肠炎方面发挥重要作用 [ 11- 12] ；TRIM25促进染色质重构复合体蛋白(chromatin remodeler polybromo-1，PBRM1)泛素化降解，促进IBD和大肠癌的发展 [ 13] ；TRIM62促进caspase活化和募集结构域9(caspase activation and recruitment domain9，CARD9)K27多聚泛素化从而活化CARD9，激活下游信号，导致大量的细胞因子产生，加重IBD的病情 [ 14] ；泛素连接酶pellino3的损失将减弱依赖NOD2途径的受体相互作用蛋白2(receptor-interacting protein 2，RIP2)的泛素化，下游NF-κB和丝裂原活化蛋白激酶活性降低，从而影响肠炎的病程 [ 15] 。总之，蛋白泛素化修饰作为一种重要的蛋白翻译后修饰，在IBD的发生、发展和转归中均发挥作用。目前，环指蛋白183(ring finger protein 183, RNF183)、RNF20、Itch和锌指蛋白A20是研究较为清楚的通过调控蛋白泛素化修饰参与IBD调控的重要分子( 图 1)，现就上述分子对IBD的调控机制进行综述。

graphic file with name zjdxxbyxb-47-1-82-1.jpg

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RNF蛋白家族由一系列含有RING结构域的蛋白质组成，其中一些成员具有泛素连接酶的作用 [ 16] 。已有研究表明，一些异常表达的环指蛋白家族成员在炎症、肿瘤的形成和发展过程中发挥一定的作用 [ 17] 。NF-κB是一种介导促炎反应高度保守的核转录因子，参与炎症、免疫应答、细胞凋亡等多种生理和病理过程 [ 6, 18] 。NF-κB信号通路失控会导致肠道产生异常的细胞因子和趋化因子，在IBD的发生和发展中扮演着关键角色。静止状态下，NF-κB二聚体与细胞质中NF-κB抑制蛋白α(IκBα)结合，以无活性的状态存在于细胞质中。受到刺激后，在IκBα激酶(IκK)作用下IκB发生磷酸化，磷酸化后的IκB在泛素化酶复合体的催化作用下被蛋白酶体降解。活化后的NF-κB由细胞质进入细胞核，启动多种炎症介质的转录，如环氧合酶2(cyclooxygenase-2，COX2)、TNF、IL-1和IL-6等，促进IBD发展。Yu等 [ 2] 研究显示，RNF183能够促进IκBα泛素化降解，NF-κB-P65表达增加，活化NF-κB途径，进而促进IBD的发生和发展；在Caco-2细胞中转染 Rnf183 +质粒，检测IL-8、IL-6、IL-1β发现IL-8上升最多。尽管该实验并没有检测TNF-α，鉴于NF-κB活性增加通常伴随着TNF-α的增加，因此我们有理由认为在该条件下TNF-α表达增加，但与IL-8的改变量差异仍有待于进一步证明。关于结肠炎相关肿瘤的研究发现，RNF183通过活化NF-κB信号通路诱导IL-8大量表达，促进肠道炎症进展和肿瘤细胞增殖、迁移和侵袭等 [ 19] 。此外，RNF183并非独自参与NF-κB途径的调控，而是依赖多种分子，其中微小RNA7(miR-7)在此过程中扮演重要的作用。相对于对照组，miR-7在IBD患者及2, 4, 6-三硝基苯磺酸诱导小鼠结肠炎的肠组织中显著减少，并且miR-7可以抑制RNF183翻译，使其活性降低，从而减轻IBD的病情 [ 2] 。曲美替尼是丝裂原活化的细胞外信号调节激酶抑制剂，临床已作为一种抗肿瘤药物，而研究表明肿瘤细胞可通过RNF183/IL-8途径减弱曲美替尼对结肠癌的治疗效果 [ 20] 。总之，RNF183不仅通过miR-7/RNF183/NF-κB途径促进了IBD的发展，还可以通过RNF183/NF-κB/IL-8途径在IBD和结肠癌中发挥关键作用。

真核生物DNA被包装在核小体中，核小体由核心组蛋白(H2A、H2B、H3、H4)组成，各种各样的组蛋白翻译后修饰对染色质动力学和转录进行调控 [ 21] 。E3泛素连接酶RNF20/RNF40复合物可介导组蛋白H2B单泛素化，形成H2Bub1。H2Bub1不仅参与细胞周期、肿瘤形成和细胞凋亡的调控，还参与染色质分离，DNA复制、转录和转录后修饰等诸多方面 [ 22] 。H2Bub1主要位于下游转录区，与促染色质转录因子和聚合酶相关因子复合物相互作用，可抑制依赖RNA聚合酶Ⅱ的转录 [ 23- 24] 。研究显示，在RNF20杂合小鼠中，肠道紧密连接蛋白表达下降，肠屏障功能较弱，更易诱导形成结肠炎，且在结肠上皮中发现较多的巨噬细胞和T细胞浸润 [ 22] 。正常情况下，H2Bub1通过改变染色质的结构，优先结合相关转录因子(其与P50同源二聚体的亲和性远大于P65-P65二聚体和P65-P50二聚体的亲和性)，抑制NF-κB信号转导，从而下调炎症因子表达。当H2Bub1下降时，染色质与P50二聚体结合下降，而与大量具有转录活性的含P65二聚体结合，依赖NF-κB信号通路相关细胞因子的基因表达增加，从而释放大量的细胞因子，促进肠道炎症的发生 [ 22] 。此外，RNF20杂合子小鼠的结肠中伴随着大量能够降低抗肿瘤性T细胞活性的髓源性抑制细胞，释放大量活性氧/一氧化氮和精氨酸酶-1等，损伤肠黏膜 [ 22] 。肠道内高水平的M2型巨噬细胞既增强了髓源性抑制细胞的活性，又形成了一个促进肿瘤形成的微环境 [ 25] 。另外，H2Bub1减少可以增加DNA损伤，从而促进结肠和直肠肿瘤的发生和发展。总之，RNF20降低导致H2Bub1下降，既增加了DNA损伤，又促进促炎细胞因子TNF-α的活性，从而上调一系列与炎症相关基因的表达，在IBD和炎症相关肠道肿瘤的发生和发展中发挥重要作用。

越来越多的研究表明，IL-17在结肠炎和肠道肿瘤形成中扮演关键角色 [ 26- 27] 。IL-17异常表达时通过诱导多种细胞因子和趋化因子产生而增强炎症反应，并通过募集中性粒细胞和巨噬细胞导致组织损伤 [ 28] 。肠道IL-17主要来源于Th17细胞、γδ-T细胞和固有淋巴样细胞。为应对微生物及其产物，髓系细胞释放IL-6和IL-23，诱导转录因子ROR-γt的表达，而ROR-γt是促进IL-17表达的关键因子 [ 29] 。Itch属于E3泛素连接酶，其缺乏会导致多器官炎症。Kathania等 [ 30] 发现，Itch缺乏会导致自发性结肠炎的发生，Itch缺乏者更易发生结肠炎相关结肠癌。在葡聚糖硫酸钠诱导的结肠上皮损伤中，小鼠Itch敲除后更易发生结肠炎，组织学检查结果显示其有严重的肠道水肿，大量单核细胞和中性粒细胞浸润，溃疡范围更大，正常肠道腺体减少更多 [ 30] 。研究表明，Itch可通过自身的WW结构域(含有两个保守的色胺酸残基)与富含PPXY保守基序的ROR-γt蛋白相互作用，促进ROR-γt发生以K48连接的多聚泛素化降解，下调IL-17的表达并减弱了其下游效应 [ 30] 。

另有研究发现，Itch可直接靶向NOD2结合蛋白和RIP2，促进其形成K63连接形式的多聚泛素化，影响炎症信号传导，在克罗恩病中发挥重要作用 [ 31] 。肠纤维化是IBD患者常见的并发症，其在克罗恩病患者中的发生率在30%以上，而在溃疡性结肠炎患者中的发病率为5% [ 32] 。肠纤维化是细胞外基质蛋白过度产生、异常分布的结果，免疫细胞释放大量的细胞因子可促进细胞外基质的产生。由于溃疡性结肠炎仅累及肠黏膜和黏膜下层，而克罗恩病涉及肠壁全层，因而后者有更多的肌成纤维细胞暴露在利于纤维化产生的环境中，致使肌成纤维细胞大量活化，因此肠纤维化在克罗恩病患者中的发生率较高 [ 32] 。过氧化氢诱导的克隆-5(hydrogen peroxide inducible clone-5, HIC-5)又名雌激素受体相关蛋白55，在肠纤维化形成中发挥一定作用。Paul等 [ 33] 证明Itch可靶向HIC-5形成以K63连接形式的多聚泛素链，以抑制IL-17介导的肠纤维化。

总之，Itch可以通过ROR-γt/IL-17途径及其与NOD2和RIP2的相互作用影响IBD发展，并可靶向HIC-5抑制IL-17介导的纤维化，在IBD病情发展和纤维化进程中均发挥重要作用。

锌指蛋白A20，又称肿瘤坏死因子α诱导蛋白3 [ 34] ，包含两种功能结构域：氨基末端包含去泛素化酶的卵巢肿瘤结构域和羧基末端包含E3连接酶的锌指结构 [ 32] 。因此，A20是一种具有泛素化和去泛素化双重酶活性的蛋白，能负调控多种信号转导途径介导的炎症反应和细胞凋亡，在炎症性疾病特别是IBD的发生、发展和转归中发挥重要作用。近年研究发现，TNF-α参与并介导的肠上皮屏障损伤在IBD的发病中扮演着关键角色，其能诱导其他多种炎性介质(如IL-1、IL-6、γ干扰素等)释放，激活全身和肠道免疫系统，引起免疫级联反应诱导肠道局部甚至全身炎症反应 [ 35] 。近年来关于IBD的大量研究结果显示，TNF-α一方面通过NF-κB/肌球蛋白轻链激酶(myosin light chain kinase, MLCK)紧密连接途径造成肠上皮细胞紧密连接蛋白重排或缺失和肠上皮通透性增加 [ 36] ，另一方面通过肿瘤坏死因子受体相关死亡域蛋白(TNF receptor associated death domain protein, TRADD)/Fas相关死亡功能域蛋白(Fas-associating death domain, FADD)细胞凋亡途径介导肠上皮细胞大量凋亡 [ 37] ，这两方面共同作用加重了肠道炎症的发展。A20可以使NF-κB信号通路的关键接头分子TNF受体相关因子6(TNF receptor-associated factor 6，TRAF6)去泛素化，同时使RIP1泛素化并降解，从而抑制NF-κB信号通路的活化 [ 38] 。此外，A20可以影响RIP、TRAF6、TRADD等接头分子在TNFR1信号复合体中的募集和信号转导 [ 39] 。因此，A20在TNF-α介导的NF-κB/MLCK途径和TRADD/FADD细胞凋亡途径中发挥负调控作用。Vereecke等 [ 40] 发现肠上皮细胞和髓系细胞特异性敲除A20的小鼠不仅产生高水平的炎症因子，而且反复形成以肠上皮细胞凋亡和高度增生为特征的肠道炎症。随着时间推移，肠道潘氏细胞和杯状细胞减少，抗菌肽和黏液分泌量下降，肠道菌群失调，细菌大量渗透到肠上皮细胞中，导致小鼠发生严重的结肠炎。随着年龄增长，小鼠肠上皮细胞高度增生，形成发育不良的肠上皮细胞，这种异常增生正是结肠癌和直肠癌典型的特征 [ 40] 。总之，A20因具有泛素化和去泛素化双重活性的特性，通过A20/NF-κB途径和A20/TRADD/FADD细胞凋亡途径在维持肠道稳态、肠道炎症方面发挥重要的作用。

蛋白泛素化修饰对IBD的调控涉及多个方面，其在发病、病情进展、疾病诊断和治疗中均发挥一定的作用。NF-κB信号通路在IBD的发病中扮演着重要的角色，泛素化修饰对此信号通路中众多分子的调控作用尚待阐明。NOD2信号通路在肠道菌群异常所致肠炎中具有保护性作用，现有研究显示E3连接酶pellino-3对此通路中激酶受体RIP2的泛素化修饰在NOD2下游信号转导发挥重要作用，但对其他分子的作用目前研究仍较少。TNF-α可抑制miR-7而上调RNF183促进IBD的发展，临床已用抗TNF-α单克隆抗体英夫利昔治疗IBD，能否找到作用于miR/RNF183途径从而缓解IBD病情的其他分子还需进一步研究。RNF183在肠炎与结直肠癌中均高表达，我们认为RNF183可能促进IBD向结直肠癌转变，因此找到抑制RNF183/NF-κB途径的分子可能为IBD和结直肠癌的治疗提供新的方向。虽已有研究证明多种E3连接酶参与其他组织中免疫紊乱导致炎性疾病产生，但对IBD的调控研究较少。通过对泛素化调控IBD的研究找到相关靶分子且进行干预，从而控制肠炎，将有助于减少相关肿瘤的发生，提高患者的生活质量。

Funding Statement

浙江省自然科学基金（LZ17H100001）；国家自然科学基金（31670914）

References

  • 1.MALOY K J, POWRIE F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474(7351):298–306. doi: 10.1038/nature10208. [MALOY K J, POWRIE F. Intestinal homeostasis and its breakdown in inflammatory bowel disease[J]. Nature, 2011, 474(7351):298-306.] [DOI] [PubMed] [Google Scholar]
  • 2.YU Q, ZHANG S, CHAO K, et al. E3 Ubiquitin ligase RNF183 is a novel regulator in inflammatory bowel disease. J Crohns Colitis. 2016;10(6):713–725. doi: 10.1093/ecco-jcc/jjw023. [YU Q, ZHANG S, CHAO K, et al. E3 Ubiquitin ligase RNF183 is a novel regulator in inflammatory bowel disease[J]. J Crohns Colitis, 2016, 10(6):713-725.] [DOI] [PubMed] [Google Scholar]
  • 3.GEREMIA A, BIANCHERI P, ALLAN P, et al. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014;13(1):3–10. doi: 10.1016/j.autrev.2013.06.004. [GEREMIA A, BIANCHERI P, ALLAN P, et al. Innate and adaptive immunity in inflammatory bowel disease[J]. Autoimmun Rev, 2014, 13(1):3-10.] [DOI] [PubMed] [Google Scholar]
  • 4.ROY U, EJC G, ILJAZOVIC A, et al. Distinct microbial communities trigger colitis development upon intestinal barrier damage via innate or adaptive immune cells. Cell Rep. 2017;21(4):994–1008. doi: 10.1016/j.celrep.2017.09.097. [ROY U, EJC G, ILJAZOVIC A, et al. Distinct microbial communities trigger colitis development upon intestinal barrier damage via innate or adaptive immune cells[J]. Cell Rep, 2017, 21(4):994-1008.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.NG S C, SHI H Y, HAMIDI N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century:a systematic review of population-based studies. http://www.ncbi.nlm.nih.gov/pubmed/29050646. Lancet. 2018;390(10114):2769–2778. doi: 10.1016/S0140-6736(17)32448-0. [NG S C, SHI H Y, HAMIDI N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century:a systematic review of population-based studies[J]. Lancet, 2018, 390(10114):2769-2778.] [DOI] [PubMed] [Google Scholar]
  • 6.CHEN J, CHEN Z J. Regulation of NF-kappaB by ubiquitination. Cur Opin Immunol. 2013;25(1):4–12. doi: 10.1016/j.coi.2012.12.005. [CHEN J, CHEN Z J. Regulation of NF-kappaB by ubiquitination[J]. Cur Opin Immunol, 2013, 25(1):4-12.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.SWATEK K N, KOMANDER D. Ubiquitin modifications. Cell Res. 2016;26(4):399–422. doi: 10.1038/cr.2016.39. [SWATEK K N, KOMANDER D. Ubiquitin modifications[J]. Cell Res, 2016, 26(4):399-422.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.SCHULMAN B A, HARPER J W. Ubiquitin-like protein activation by E1 enzymes:the apex for downstream signalling pathways. http://europepmc.org/articles/PMC2712597. Nat Rev Mol Cell Biol. 2009;10(5):319–331. doi: 10.1038/nrm2673. [SCHULMAN B A, HARPER J W. Ubiquitin-like protein activation by E1 enzymes:the apex for downstream signalling pathways[J]. Nat Rev Mol Cell Biol, 2009, 10(5):319-331.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.YE Y, RAPE M. Building ubiquitin chains:E2 enzymes at work. Nat Rev Mol Cell Biol. 2009;10(11):755–764. doi: 10.1038/nrm2780. [YE Y, RAPE M. Building ubiquitin chains:E2 enzymes at work[J]. Nat Rev Mol Cell Biol, 2009, 10(11):755-764.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.DESHAIES R J, JOAZEIRO C A. RING domain E3 ubiquitin ligases. Annu Rev Biochem. 2009;78:399–434. doi: 10.1146/annurev.biochem.78.101807.093809. [DESHAIES R J, JOAZEIRO C A. RING domain E3 ubiquitin ligases[J]. Annu Rev Biochem, 2009, 78:399-434.] [DOI] [PubMed] [Google Scholar]
  • 11.SONG H, LIU B, HUAI W, et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat Commun. 2016;7:13727. doi: 10.1038/ncomms13727. [SONG H, LIU B, HUAI W, et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3[J]. Nat Commun, 2016, 7:13727.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.ZAKI M H, BOYD K L, VOGEL P, et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity. 2010;32(3):379–391. doi: 10.1016/j.immuni.2010.03.003. [ZAKI M H, BOYD K L, VOGEL P, et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis[J]. Immunity, 2010, 32(3):379-391.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.SHU X S, ZHAO Y, ZHONG L, et al. The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-l-like receptor signalling and is a potential prognostic biomarker for colon cancer. J Pathol. 2018;244(1):36–48. doi: 10.1002/path.4986. [SHU X S, ZHAO Y, ZHONG L, et al. The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-l-like receptor signalling and is a potential prognostic biomarker for colon cancer[J]. J Pathol, 2018, 244(1):36-48.] [DOI] [PubMed] [Google Scholar]
  • 14.CAO Z, CONWAY K L, HEATH R J, et al. Ubiquitin ligase TRIM62 regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. Immunity. 2015;43(4):715–726. doi: 10.1016/j.immuni.2015.10.005. [CAO Z, CONWAY K L, HEATH R J, et al. Ubiquitin ligase TRIM62 regulates CARD9-mediated anti-fungal immunity and intestinal inflammation[J]. Immunity, 2015, 43(4):715-726.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.YANG S, WANG B, HUMPHRIES F, et al. Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis. Nat Immunol. 2013;14(9):927–936. doi: 10.1038/ni.2669. [YANG S, WANG B, HUMPHRIES F, et al. Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis[J]. Nat Immunol, 2013, 14(9):927-936.] [DOI] [PubMed] [Google Scholar]
  • 16.NAKAMURA N. The role of the transmembrane RING finger proteins in cellular and organelle function. http://www.mdpi.com/2077-0375/1/4/354. Membranes(Basel) 2011;1(4):354–393. doi: 10.3390/membranes1040354. [NAKAMURA N. The role of the transmembrane RING finger proteins in cellular and organelle function[J]. Membranes(Basel), 2011, 1(4):354-393.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.HEUZÉ M L, LAMSOUL I, MOOG-LUTZ C, et al. Ubiquitin-mediated proteasomal degradation in normal and malignant hematopoiesis. Blood Cells Mol Dis. 2008;40(2):200–210. doi: 10.1016/j.bcmd.2007.07.011. [HEUZÉ M L, LAMSOUL I, MOOG-LUTZ C, et al. Ubiquitin-mediated proteasomal degradation in normal and malignant hematopoiesis[J]. Blood Cells Mol Dis, 2008, 40(2):200-210.] [DOI] [PubMed] [Google Scholar]
  • 18.DUTTA J, FAN Y, GUPTA N, et al. Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene. 2006;25(51):6800–6816. doi: 10.1038/sj.onc.1209938. [DUTTA J, FAN Y, GUPTA N, et al. Current insights into the regulation of programmed cell death by NF-kappaB[J]. Oncogene, 2006, 25(51):6800-6816.] [DOI] [PubMed] [Google Scholar]
  • 19.GENG R, TAN X, WU J, et al. RNF183 promotes proliferation and metastasis of colorectal cancer cells via activation of NF-kappaB-IL-8 axis. Cell Death Dis. 2017;8(8):e2994. doi: 10.1038/cddis.2017.400. [GENG R, TAN X, WU J, et al. RNF183 promotes proliferation and metastasis of colorectal cancer cells via activation of NF-kappaB-IL-8 axis[J/OL]. Cell Death Dis, 2017, 8(8):e2994.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.GENG R, TAN X, ZUO Z, et al. Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells. Chin J Cancer. 2017;36(1):63. doi: 10.1186/s40880-017-0228-1. [GENG R, TAN X, ZUO Z, et al. Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells[J]. Chin J Cancer, 2017, 36(1):63.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.CAMPOS E I, REINBERG D. Histones:annotating chromatin. Annu Rev Genet. 2009;43:559–599. doi: 10.1146/annurev.genet.032608.103928. [CAMPOS E I, REINBERG D. Histones:annotating chromatin[J]. Annu Rev Genet, 2009, 43:559-599.] [DOI] [PubMed] [Google Scholar]
  • 22.TARCIC O, PATERAS I S, COOKS T, et al. RNF20 links histone H2B ubiquitylation with inflammation and inflammation-associated cancer. Cell Rep. 2016;14(6):1462–1476. doi: 10.1016/j.celrep.2016.01.020. [TARCIC O, PATERAS I S, COOKS T, et al. RNF20 links histone H2B ubiquitylation with inflammation and inflammation-associated cancer[J]. Cell Rep, 2016, 14(6):1462-1476.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.MINSKY N, SHEMA E, FIELD Y, et al. Monoubiquitinated H2B is associated with the transcribed region of highly expressed genes in human cells. Nat Cell Biol. 2008;10(4):483–488. doi: 10.1038/ncb1712. [MINSKY N, SHEMA E, FIELD Y, et al. Monoubiquitinated H2B is associated with the transcribed region of highly expressed genes in human cells[J]. Nat Cell Biol, 2008, 10(4):483-488.] [DOI] [PubMed] [Google Scholar]
  • 24.PAVRI R, ZHU B, LI G, et al. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase Ⅱ. Cell. 2006;125(4):703–717. doi: 10.1016/j.cell.2006.04.029. [PAVRI R, ZHU B, LI G, et al. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase Ⅱ[J]. Cell, 2006, 125(4):703-717.] [DOI] [PubMed] [Google Scholar]
  • 25.KATOH H, WANG D, DAIKOKU T, et al. CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell. 2013;24(5):631–644. doi: 10.1016/j.ccr.2013.10.009. [KATOH H, WANG D, DAIKOKU T, et al. CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis[J]. Cancer Cell, 2013, 24(5):631-644.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.WU P, WU D, NI C, et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity. 2014;40(5):785–800. doi: 10.1016/j.immuni.2014.03.013. [WU P, WU D, NI C, et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer[J]. Immunity, 2014, 40(5):785-800.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.GRIVENNIKOV S I, WANG K, MUCIDA D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 2012;491(7423):254–258. doi: 10.1038/nature11465. [GRIVENNIKOV S I, WANG K, MUCIDA D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth[J]. Nature, 2012, 491(7423):254-258.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.DONG C. Th17 cells in development:an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008;8(5):337–348. doi: 10.1038/nri2295. [DONG C. Th17 cells in development:an updated view of their molecular identity and genetic programming[J]. Nat Rev Immunol, 2008, 8(5):337-348.] [DOI] [PubMed] [Google Scholar]
  • 29.ZHANG F, MENG G, STROBER W. Interactions among the transcription factors Runx1, RORγ and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat Immunol. 2008;9(11):1297–1306. doi: 10.1038/ni.1663. [ZHANG F, MENG G, STROBER W. Interactions among the transcription factors Runx1, RORγ and Foxp3 regulate the differentiation of interleukin 17-producing T cells[J]. Nat Immunol, 2008, 9(11):1297-1306.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.KATHANIA M, KHARE P, ZENG M, et al. Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-gammat ubiquitination. Nat Immunol. 2016;17(8):997–1004. doi: 10.1038/ni.3488. [KATHANIA M, KHARE P, ZENG M, et al. Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-gammat ubiquitination[J]. Nat Immunol, 2016, 17(8):997-1004.] [DOI] [PubMed] [Google Scholar]
  • 31.TAO M, SCACHERI P C, MARINIS J M, et al. ITCH directly K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol. 2009;19(15):1255–1263. doi: 10.1016/j.cub.2009.06.038. [TAO M, SCACHERI P C, MARINIS J M, et al. ITCH directly K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways[J]. Curr Biol, 2009, 19(15):1255-1263.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.LATELLA G, DI G J, FLATI V, et al. Mechanisms of initiation and progression of intestinal fibrosis in IBD. Scand J Gastroenterol. 2015;50(1):53–65. doi: 10.3109/00365521.2014.968863. [LATELLA G, DI G J, FLATI V, et al. Mechanisms of initiation and progression of intestinal fibrosis in IBD[J]. Scand J Gastroenterol, 2015, 50(1):53-65.] [DOI] [PubMed] [Google Scholar]
  • 33.PAUL J, SINGH A K, KATHANIA M, et al. IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5. Mucosal Immunol. 2018;11(2):427–436. doi: 10.1038/mi.2017.53. [PAUL J, SINGH A K, KATHANIA M, et al. IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5[J]. Mucosal Immunol, 2018, 11(2):427-436.] [DOI] [PubMed] [Google Scholar]
  • 34.VEREECKE L, BEYAERT R, VAN LOO G. The ubiquitin-editing enzyme A20(TNFAIP3) is a central regulator of immunopathology. Trends Immunol. 2009;30(8):383–391. doi: 10.1016/j.it.2009.05.007. [VEREECKE L, BEYAERT R, VAN LOO G. The ubiquitin-editing enzyme A20(TNFAIP3) is a central regulator of immunopathology[J]. Trends Immunol, 2009, 30(8):383-391.] [DOI] [PubMed] [Google Scholar]
  • 35.HOLLERAN G, LOPETUSO L, PETITO V, et al. The innate and adaptive immune system as targets for biologic therapies in inflammatory bowel disease. Int J Mol Sci. 2017;18(10):2020. doi: 10.3390/ijms18102020. [HOLLERAN G, LOPETUSO L, PETITO V, et al. The innate and adaptive immune system as targets for biologic therapies in inflammatory bowel disease[J/OL]. Int J Mol Sci, 2017, 18(10):2020.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.YE D, MA I, MA T Y. Molecular mechanism of tumor necrosis factor-alpha modulation of intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol. 2006;290(3):G496–G504. doi: 10.1152/ajpgi.00318.2005. [YE D, MA I, MA T Y. Molecular mechanism of tumor necrosis factor-alpha modulation of intestinal epithelial tight junction barrier[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 290(3):G496-G504.] [DOI] [PubMed] [Google Scholar]
  • 37.BAO C H, WU L Y, SHI Y, et al. Moxibustion down-regulates colonic epithelial cell apoptosis and repairs tight junctions in rats with Crohn's disease. World J Gastroenterol. 2011;17(45):4960–4970. doi: 10.3748/wjg.v17.i45.4960. [BAO C H, WU L Y, SHI Y, et al. Moxibustion down-regulates colonic epithelial cell apoptosis and repairs tight junctions in rats with Crohn's disease[J]. World J Gastroenterol, 2011, 17(45):4960-4970.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.EVANS P C, OVAA H, HAMON M, et al. Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity. https://www.ncbi.nlm.nih.gov/pubmed/14748687. Biochem J. 2004;378(Pt 3):727–734. doi: 10.1042/BJ20031377. [EVANS P C, OVAA H, HAMON M, et al. Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity[J]. Biochem J, 2004, 378(Pt 3):727-734.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.KOLODZIEJ L E, LODOLCE J P, CHANG J E, et al. TNFAIP3 maintains intestinal barrier function and supports epithelial cell tight junctions. PLoS One. 2011;6(10):e26352. doi: 10.1371/journal.pone.0026352. [KOLODZIEJ L E, LODOLCE J P, CHANG J E, et al. TNFAIP3 maintains intestinal barrier function and supports epithelial cell tight junctions[J/OL]. PLoS One, 2011, 6(10):e26352.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.VEREECKE L, VIEIRA-SILVA S, BILLIET T, et al. A20 controls intestinal homeostasis through cell-specific activities. Nat Commun. 2014;5:5103. doi: 10.1038/ncomms6103. [VEREECKE L, VIEIRA-SILVA S, BILLIET T, et al. A20 controls intestinal homeostasis through cell-specific activities[J]. Nat Commun, 2014, 5:5103.] [DOI] [PubMed] [Google Scholar]

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