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微小RNA在病毒与宿主相互作用中的功能

2017-03-08魏建春安静

微生物与感染 2017年1期
关键词:疱疹病毒宿主编码

魏建春,安静

首都医科大学病原生物学教研室,北京 100069

·综述·

微小RNA在病毒与宿主相互作用中的功能

魏建春,安静

首都医科大学病原生物学教研室,北京 100069

微小RNA(microRNA,miRNA)是一类长度为22个核苷酸左右的内源性非编码小RNA分子。自1993年最先从秀丽隐杆线虫体内发现miRNA以来,目前为止已有35 000多条miRNA在植物、动物及病毒中被发现。它们作为重要的转录调控因子,参与细胞分化、凋亡、代谢、信号转导、免疫等多种生物学过程。病毒和宿主细胞均可编码miRNA,病毒编码的miRNA可改变宿主内环境,而宿主编码的miRNA则可影响病毒生存。本文就miRNA对病毒与宿主相互作用的调控进行综述。

微小RNA;疱疹病毒;肿瘤;病毒-宿主相互作用

1 微小RNA

微小RNA(microRNA,miRNA)是一类长度为22个核苷酸(nucleotide,nt)左右的内源性非编码小RNA分子,在动植物体内发挥重要的生物学作用[1-2]。最早揭开miRNA序幕的是哈佛大学的Lee等,他们在1993年指出lin-4基因可编码一段22 nt的RNA片段,通过调控靶基因lin-14而控制秀丽隐杆线虫的发育时序[3]。7年后,Reinhart等报道let-7可编码长度为21 nt的RNA片段,通过与靶基因的3′非编码区(3′-untranslated region,3′-UTR)相结合,控制秀丽隐杆线虫从幼虫到成虫的转变[4]。随着检测技术的不断提高,人们发现不仅在线虫,果蝇、鱼和哺乳动物等均有miRNA存在,从而开启了miRNA研究的热潮[5-7]。miRBase数据库(www.mirbase.org)统计显示,目前已发现的miRNA在223个物种中存在,共有发夹前体miRNA(pre-miRNA)28 645条,成熟miRNA序列35 828条。在人等脊椎动物中,miRNA分布于胚胎、造血干细胞、肝脏、心脏、脑等多种组织和细胞中。

miRNA的转录单位通常是一段独立的基因,可位于编码蛋白基因的内含子中,也可位于外显子中[8]。经典理论认为,miRNA的生物学发生首先由转录单位在细胞核中被RNA聚合酶Ⅱ转录为原始miRNA(primary miRNA,pri-miRNA),其长度较长,可超过1 kb。其后在核酸酶Drosha及其辅助因子Pasha作用下,pri-miRNA被剪切成60~70 nt的发夹结构,形成pre-miRNA。这些pre-miRNA由Exportin-5输送至细胞质中,进一步被Dicer(RNase Ⅲ家族)剪切,形成约22 bp的双链RNA复合体。经解螺旋酶作用后,5′端具有低稳定性的引导链被优先选择,与细胞质中的Ago等蛋白结合,形成RNA诱导的沉默复合体(RNA-induced silencing complex,RISC)[2,9]。在RISC中,miRNA发育成熟,参与基因转录后调节。调节机制一般有两种,即靶向识别降解和转录抑制。前者主要存在于植物中,后者则多见于动物中。miRNA通过“种子区”(seed region;第2~7位碱基)与靶mRNA的3′-UTR互补结合,进而影响基因的表达[10]。近几年研究显示,miRNA在动物中不仅可引起mRNA转录抑制,有些miRNA还可促进靶基因转录[11-12]。

miRNA在染色体上是非随机分布的,许多miRNA基因紧密连接,成簇排列[13-14]。成簇排列的miRNA即使序列不同,调节功能仍可相似。这种基因簇排列方式提示miRNA有复杂的调控机制。此外,miRNA在不同物种之间高度保守,这种保守性不仅体现在序列上,在二级结构中也有所表现。同源性越近,miRNA之间保守性越明显[15-17]。

miRNA在表达上有几个明显特征。首先,其具有明显的细胞和组织特异性[18]。2005年Wienholds等研究发现,斑马鱼(zebrafish)体内多数(68%)miRNA均有组织学特异性,推测miRNA参与组织的分化和特征维持[19]。在其他动物中也观察到相似现象,如miR-1主要在心脏中表达[7],miR-122主要在肝脏中表达[20],miR-223主要在造血系统中表达等[21]。其次,miRNA的表达具有时序性。miR-35-miR-41基因簇只在秀丽隐杆线虫胚胎和幼虫期表达[6];miR-290-miR-295仅存在于小鼠胚胎干细胞,在其他发育阶段并没有发现[22]。由此推测,在生物不同发展阶段miRNA有其特定的表达模式。最后,细胞中不同miRNA表达量可非常高或非常低。Lim等在研究秀丽隐杆线虫时发现,每个细胞中miR-2、miR-52、miR-58可表达50 000个分子,甚至高于U6的表达量;而miR-124低表达,每个细胞中只有800个[23]。造成这种差异的机制有待进一步研究。

随着miRNA研究的深入及其发现数量越来越多,人们对miRNA关注的焦点逐渐转向作用机制,尤其是与人类疾病相关方面[24-25]。现已证明miRNA在细胞分化和凋亡、代谢、信号转导、免疫和移形等方面均扮演着重要角色,其表达异常与肿瘤、病毒感染、免疫性疾病、神经退行性病变等疾病密切相关。在病毒感染过程中,miRNA作为关键效应分子,在宿主-抗原相互作用中发挥重要功能。病毒和宿主均可编码miRNA,病毒编码的miRNA有助于病毒实现免疫逃逸,而宿主编码的miRNA则对病毒感染有促进或抑制作用。

2 病毒miRNA

miRNA可由病毒编码而来,主要集中于疱疹病毒科、多瘤病毒科和反转录病毒科。这些可编码miRNA的病毒绝大多数是双链DNA(double-stranded DNA,dsDNA)病毒[26-28]。除少数几种病毒〔鼠疱疹病毒(murine herpesvirus,MHV)、腺病毒和卡波西肉瘤相关疱疹病毒(Kaposi’s sarcoma-associated herpesvirus,KSHV)〕外,大多数病毒编码miRNA的过程与真核细胞类似,由转录单位或内含子通过RNA聚合酶Ⅱ转录而来。不同的是,病毒编码的miRNA分子之间同源性并不明显[26]。

2.1 疱疹病毒科

疱疹病毒根据理化性质不同分为α、β和γ 3个亚科,包括α亚科的单纯疱疹病毒(herpes simplex virus,HSV)1型和2型,β亚科的人巨细胞病毒(human cytomegalovirus,HCMV)和γ亚科的人EB病毒(Epstein-Barr virus,EBV)、KSHV及MHV68[29],可导致从轻微感染至癌症形成等多种病变。

疱疹病毒是病毒编码miRNA的主要来源。HSV分为HSV-1和HSV-2两个亚型,一般经呼吸道、生殖器黏膜及破损皮肤进入体内而潜伏感染,是最早发现的人类疱疹病毒。测序发现,人和小鼠HSV-1可编码7种miRNA,其中6种局限于非编码潜伏相关转录子(latency-associated transcript,LAT)中,另一种(miR-H1)则可在进行复制的细胞中表达。这些miRNA参与病毒潜伏状态维持及避免遭受机体免疫系统清除[30-31]。HSV-2编码的miRNA有5种,均局限于LAT中[32-33]。HCMV在人群中感染非常普遍,但大多表现为隐性感染。不同于HSV,HCMV编码的miRNA分散排列在整个基因组中,这些miRNA在细胞复制的早期出现,提示可能参与细胞周期的调节。有研究指出,HCMV可通过编码miR-UL112下调主要组织相容性复合体(major histocompatibility complex,MHC)Ⅰ类链相关蛋白B的表达,减少其与自然杀伤(natural killer,NK)细胞活化性受体NKG2D结合,降低NK细胞对HCMV的杀伤效应[34-35]。EBV与鼻咽癌(nasopharyngeal carcinoma,NPC)、Burkitt淋巴瘤(Burkitt lymphoma,BL)、胃癌(gastric cancer,GC)等多种肿瘤的发生有关。病毒可编码miRNA的现象,最早于研究RNA干扰EBV感染人B细胞过程中发现[36]。已知EBV可编码至少25种miRNA,分为BHRF1和BART两组。BHRF1组miRNA选择性高表达于EBV 3期潜伏感染细胞中,如淋巴母细胞(lymphoblastoid cell line,LCL)和BL等B细胞中;在1期或2期潜伏感染阶段(如NPC)的细胞中检测不到。BART组miRNA在病毒潜伏感染的B细胞中也可检测到,但主要高表达于2期潜伏感染的NPC上皮细胞中。由此推测,miRNA可能参与EBV感染过程中靶细胞的转移和分化[37]。KSHV可引起卡波西肉瘤、原发性渗出性淋巴瘤(primary exudative lymphoma,PEL)等病变。目前发现KSHV可编码12条miRNA,编码基因主要位于非编码区长度约4.5 kb的v-cyclin与K12/Kaposin之间。其中miR-K1-K9及miR-K11位于ORF71与kaposirr之间,剩余两条则分别位于基因组编码区(miR-K10)和KSHVK12基因3′-UTR区(miR-K12)。研究发现,miR-K10、miR-K12与另外10种miRNA在病毒裂解性复制过程中表达水平不同,推测它们在病毒不同周期所起的作用不同,但具体机制有待研究[29]。计算机预测发现,miRNA可能的靶基因中包括多种KSHV感染相关的mRNA,提示它们可能还参与细胞凋亡、信号转导、B细胞调控等多种生物学过程[38]。MHV68不仅能感染实验小鼠,还能在体外感染多B细胞系、骨髓细胞系及哺乳动物的成纤维细胞和上皮细胞等。Pfeffer等研究发现,MHV68可编码至少9种miRNA,由RNA聚合酶Ⅲ转录而来,成簇聚集在病毒线性基因组M1蛋白编码区[39]。这些结果提示,miRNA的转录可能存在多种方式[36]。

2.2 多瘤病毒科

多瘤病毒科因其能诱导机体产生多种肿瘤而得名,包括猴空泡病毒40 (simian vacuolating virus 40或simian virus 40,SV40)、鼠多瘤病毒(murine polyomavirus)、人多瘤病毒(多瘤病毒、JC多瘤病毒)等。最具代表性的为SV40。研究发现,SV40在感染后期可编码miR-S1。不同于疱疹病毒来源的miRNA,miR-S1是第1个作用靶点明确的miRNA[40]。miR-S1并不影响病毒复制,其与病毒感染早期产生的靶mRNA几乎完全互补结合使之被清除,从而降低病毒T抗原表达。该过程有助于病毒伪装,逃脱宿主特异性细胞毒性T细胞(cytotoxic T lymphocyte,CTL)识别、杀伤、破坏病毒感染细胞等免疫反应。研究多瘤病毒时也发现,miRNA可与靶mRNA结合,降低病毒抗原表达,逃逸宿主免疫反应[41]。

2.3 反转录病毒科

反转录病毒是一种有包膜的RNA病毒。目前关于RNA病毒编码miRNA的研究仍处于起步阶段。人类免疫缺陷病毒1型(human immunodeficiency virus type 1,HIV-1)属慢病毒亚科,可编码长度约50 nt的反式激活效应元件(trans-activation responsive element,TAR)片段。Klase等用生物素标记证实TAR可被细胞Dicer酶剪切,形成病毒miRNA[42]。Ouellet等也通过实验证实TAR是病毒miRNA的来源[43]。人们推测HIV-1编码的miRNA可能通过改变宿主T细胞、巨噬细胞和树突细胞活性,阻断CD28、CD4和其他一些细胞因子产生,从而帮助HIV建立和维持潜伏感染及再激发的过程[44-45]。

2.4 其他

腺病毒是无包膜的dsDNA病毒,可感染机体多脏器,如呼吸道、胃肠道、肝脏和眼等。腺病毒感染宿主后,可产生长度约160 nt富含CG的RNA聚合酶Ⅲ转录产物[46-47]。其结构类似于pre-miRNA,可在不需病毒复制和蛋白表达的条件下被输送至细胞质中剪切为小病毒相关RNA分子(small virus-associated RNA,svaRNA)。在RISC中svaRNA与Argonaute 2结合,抑制其互补序列的表达。若该过程被阻断,腺病毒的感染效率降低,提示svaRNA 参与腺病毒感染[48]。目前尚未证实其他病毒有编码病毒miRNA的能力[29],但随着技术进步,相信会有更多可编码miRNA的病毒被发现。

3 宿主miRNA

宿主编码的miRNA除调节功能外,还有抗病毒作用。哺乳类动物中这一作用的研究还处于起步阶段。Lecellier等研究发现,哺乳类动物细胞可通过编码miR-32抑制灵长类泡沫病毒1 型(primate foamy virus 1,PFV-1)的聚集[49]。Triboulet等则发现细胞编码miRNA可抑制HIV复制[50]。宿主感染病毒后,宿主miRNA表达会发生很大变化。尽管这种变化的发生机制尚不清楚,但可以肯定宿主编码miRNA与病毒所致疾病密切相关[29,51-53]。

3.1 宿主miRNA与肿瘤

EBV潜伏膜蛋白1(latent membrane protein 1,LMP1)可阻断正常信号转导通路〔如核因子κB(nuclear factor κB,NF-κB)、活化蛋白1(activator protein 1,AP-1)〕,调控细胞的生长周期,在EBV相关疾病尤其是恶性肿瘤的发展、侵袭中起重要作用。Cameron等研究发现,在EBV潜伏感染细胞中,LMP1可通过诱导miR-146a基因启动子区的两个NF-κB结合位点,使其表达上调[54];miR-146a异常表达会导致肿瘤发生[55-57]。Anastasiadou等研究发现,EBV感染BL细胞系过程中,LMP1可通过C端两个重要功能区域C 端活化区域1(carboxyl-terminal activating region 1,CTAR1;第187~231位氨基酸残基)和CTAR2(第352~386位氨基酸残基)使miR-29b表达上调,进而抑制原癌基因TCL1(T-cell leukemia gene 1)[58]。有意思的是,EBV编码的BART组miRNA可与LMP1基因组3′-UTR结合,调节LMP1表达,表明在EBV与肿瘤发病的关系中,既有病毒编码miRNA的参与,也有宿主编码miRNA的调节[59]。

除EBV外,其他病毒感染也可导致宿主miRNA表达量发生变化,引起肿瘤形成。例如,人乳头瘤病毒(human papillomavirus,HPV)编码病毒E6蛋白抑制p53基因早有报道。近年来又发现p53能直接与miR-34a第一外显子内的靶序列相结合,促进miR-34a的转录。p53基因表达或功能异常会导致其对miR-34a的刺激信号减少,降低miR-34a表达,最终造成细胞无限增殖和肿瘤形成[60]。人T细胞白血病病毒1型(human T-cell leukemia virus 1,HTLV-1)感染人体后引起miR-93和miR-130b表达上调,其3′-UTR可与抑癌蛋白TP53INP1(tumor protein 53-induced nuclear protein 1)结合,使其表达下调,最终引起成人T细胞白血病(adult T-cell leukemia,ATL)[61]。

3.2 宿主miRNA与病毒感染

宿主编码miRNA除与肿瘤相关外,还参与病毒感染的致病过程。miR-199a-3p和miR-210可分别作用于乙型肝炎病毒(hepatitis B virus,HBV)的S和前S基因,抑制病毒复制,减少HBV表面抗原(HBV surface antigen,HBsAg)的表达而不影响细胞增殖。miR-1虽然不能直接作用于HBV,但可调节宿主基因,间接促进HBV复制、转录、抗原表达和产物分泌[62-63]。miR-24和miR-93可与水疱性口炎病毒(vesicular stomatitis virus, VSV)基因组中编码L蛋白和P蛋白的区域相结合,从而干扰病毒复制[64]。miR-370可通过与其受体核因子IA(nuclear factor IA,NFIA)结合,抑制HBV基因的表达和复制[65]。miR-28、miR-125b、miR-150、miR-223 和miR-382等多种宿主miRNA可被HIV-1调控而高表达,进而降低HIV-1转录水平,导致病毒在CD4+T细胞中潜伏感染[66]。miRNA还可靶向结合HIV-1基因组,这些基因组高度保守,其中miR-29a和miR-29b结合nef基因,miR-149结合vpr基因,miR-378结合env基因,miR-324-5p结合vif基因。这5种miRNA均在HIV-1感染的T细胞中表达,提示其与HIV-1感染密切相关[67]。宿主感染甲型流感病毒后,miR-29表达上调约50倍,抑制DNA甲基转移酶(DNA methyltransferase,DNMT)活性,进一步诱导环氧化酶2(cyclooxygenase 2,COX2),启动信号转导途径,最终达到抗病毒的作用[68]。在脊髓灰质炎病毒疫苗研制过程中,miR-555因可降低病毒复制所需的核不均一核糖核蛋白(heterogeneous nuclear ribonucleoprotein,hnRNP) C1/C2复制水平而表现出抗病毒活性[69]。

3.3 宿主miRNA的应用

宿主编码的miRNA在临床上有较好的应用前景。① miRNA的变化可体现临床预后。高致病性流感病毒感染时机体中某些miRNA分子表达异常,而在其他非致命性病原感染时表达无明显变化。如miR-21和miR-223分别在H5N1禽流感病毒和高致病性甲型H1N1流感病毒感染时明显上调。这些miRNA分子与宿主体内的细胞因子相互作用,影响炎症反应和细胞凋亡,预后不良[70-71]。②miRNA可作为疾病分子诊断指标。miRNA相比于蛋白质等其他诊断指标有许多优点,如血液、尿液中miRNA稳定性强;样本采集方便,用量少;miRNA出现变化的时间早,有助于疾病的早期诊断。miRNA在组织中有相对特异的表达,为其在诊断中的应用提供了理论依据[24]。③miRNA可作为抗病毒治疗药物。miRNA药物的研发目前仍处于起步阶段,仅丹麦Santaris Pharma公司宣布其研制的锁核酸(locked nucleic acid,LNA)SPC3649有作为抗病毒药物的应用前景。SOC3649是miR-122拮抗剂,可与miR-122的5′-UTR结合,抑制miR-122-HCV复合物形成,从而抑制病毒复制。目前该药物正在美国、荷兰、德国、波兰、罗马尼亚和斯洛伐克进行Ⅱ期临床试验,并展现出很好的抗病毒效果[72-75]。

4 结语

miRNA分子是由RNA聚合酶Ⅱ/Ⅲ转录而来的长度约22 nt的内源性非编码小RNA分子,其可与靶mRNA结合,参与基因的转录后调节。miRNA调控通路的发现使人们以全新的视角重新审视病毒与宿主的相互关系。病毒编码的miRNA可降低其对宿主CTL、NK细胞的敏感性,逃避免疫反应;有的甚至可对病毒自身复制起正调控作用。宿主编码的大多数miRNA可起保护作用,其表达失调可导致肿瘤形成和抗病毒能力减弱。少数miRNA可与靶基因5′-UTR结合,促进病毒复制。目前,人们已尝试利用miRNA进行疾病诊断和药物治疗。相信随着研究的深入,会有更多的基于miRNA的抗病毒预防和治疗策略被发现。

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. AN Jing, E-mail: anjing@ccmu.edu.cn

Functions of microRNAs in virus-host interactions

WEI Jianchun, AN Jing

InstituteofPathogenicBiology,CapitalMedicalUniversity,Beijing100069,China

microRNAs (miRNAs) are a class of non-coding small RNAs with the length of about 22 nucleotides. More than 35 000 miRNAs have been found in plants, animals and viruses since its discovery inCaenorhabditiselegansin 1993. They participate in a variety of biological processes involved in cell differentiation, apoptosis, metabolism, signal transduction, immune responses, and act as critical transcription factors. miRNAs can be encoded both by viruses and host cells. Virus-encoded miRNAs can alter the internal environment of host, and host-encoded miRNAs also have effect on survival of virus. This article aims to review the functions of miRNAs in virus-host interactions.

microRNA; Herpes virus; Tumor; Virus-host interaction

国家自然科学基金(81271839、81471957)

安静

2015-12-03)

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