原核細胞microRNA特性及其作用機制研究進展

張新蔚，黃燕穎，嚴 杰，孫愛華

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原核細胞microRNA特性及其作用機制研究進展

張新蔚1,3，黃燕穎1,3，嚴 杰2，孫愛華3

microRNA為一類非編碼小RNA，主要通過其種子序列(seed sequence，SS)與靶mRNA位于5′端的SS結合序列特異性結合后抑制靶mRNA轉錄或降解靶mRNA，從而在轉錄后水平負調(diào)控靶基因表達。microRNA首先發(fā)現(xiàn)于秀麗隱桿線蟲(Caenorhabditiselegans)，此后發(fā)現(xiàn)各種真核細胞均存在大量各種microRNA。真核細胞首先轉錄出microRNA前體，經(jīng)剪切后成為21～23 nt有功能的microRNA，大多與靶mRNA的3′端序列結合后引起靶mRNA翻譯抑制或降解。近年不少細菌等原核細胞microRNA被發(fā)現(xiàn)，但原核細胞microRNA不需剪切即有活性，大小為50～400 nt，其特性、作用位點和機制等也與真核細胞有一定差異。本文簡要介紹真核和原核細胞基因表達調(diào)控主要機制、microRNA特點及其調(diào)控基因表達的機制，以期為深入研究原核細胞型病原微生物基因表達調(diào)控與致病機制奠定基礎。

原核細胞；基因表達；調(diào)控；microRNA；作用機制

Supported by the National Natural Science Foundation of China (No. 81271893) and the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (No. 2012-241) Corresponding author: Sun Ai-hua,Email: sunah123@126.com

生物大分子有蛋白、多糖、核酸及其復合物，在生命體生理或病理過程中發(fā)揮關鍵作用。基因是DNA分子中攜帶遺傳信息的片段，其表達產(chǎn)物為蛋白或多肽。酶是一類具有催化功能的蛋白，上述生物大分子合成與降解均依賴于酶的作用。因此，了解基因表達調(diào)控的物質(zhì)基礎及其工作機制具有重要意義。基因表達過程分為mRNA轉錄和翻譯(轉錄后)兩大環(huán)節(jié)。轉錄因子(transcription factor，TF)是能與DNA結合并在轉錄水平上靶基因表達的蛋白，但近年發(fā)現(xiàn)一類稱之為microRNA的非編碼小RNA也能在轉錄后水平上調(diào)控靶基因表達。本文簡要介紹真核或原核細胞TF尤其是microRNA調(diào)控靶基因表達的主要機制及其差異。

1 TF調(diào)控靶基因表達的主要機制

一般認為，真核或原核細胞基因表達調(diào)控主要依賴于TF，microRNA通常僅有微調(diào)作用。一個基因編碼的蛋白對該基因或另一基因表達的調(diào)節(jié)作用分別稱為順式或反式調(diào)節(jié)作用，包括基因轉錄的開啟和關閉。

1.1 真核細胞TF調(diào)控靶基因表達機制[1-7]在真核細胞中，順式作用元件(cis-acting element)和反式作用因子(trans-acting factor)及其相互作用是轉錄水平調(diào)控基因表達的基本機制。順式作用元件為位于基因旁側、可調(diào)控或影響該基因表達的特殊序列，根據(jù)功能不同可分為啟動子(promotor)、增強子(enhanser)、沉默子(silencer)應答元件(response element)。反式作用因子能直接或間接識別并結合另一基因順式作用元件核心序列、調(diào)控該基因轉錄水平或過程，以TF最為重要和常見。TF特異性識別靶基因啟動子區(qū)中TF結合位點(TF-binding site，TFBS)并與之結合，激活或抑制基因轉錄。多個TFBS可組成順式調(diào)節(jié)模塊(cis-regulatory modules，CRM)，大多數(shù)基因表達由多種TF通過CRM調(diào)控，一個TF也可通過不同的CRM調(diào)控多個基因表達。根據(jù)功能不同，TF可分為轉錄激活子(transcription activator)和后者稱轉錄抑制子(transcription inhibitor)，前者為增強子結合蛋白(enhancer-binding protein，EBP)，與增強子序列結合后上調(diào)基因表達，后者屬于沉默子結合蛋白(silencer-binding protein，SBP)，與沉默子序列結合后下調(diào)基因表達。增強子和沉默子序列位于轉錄起始點一定距離外(1-30 kb)，其作用不受序列方向的影響，也可對異源基因發(fā)揮作用。此外，TF對某一靶基因表現(xiàn)為表達上調(diào)作用，但對另一靶基因可呈現(xiàn)為表達抑制作用。

1.2 原核細胞基因表達調(diào)控主要機制[6-11]大多數(shù)原核細胞通過操縱子調(diào)控基因表達。操縱子由結構基因和調(diào)控序列組成，前者常為功能上有關聯(lián)、串聯(lián)排列的數(shù)個基因，共同構成編碼區(qū)，后者包括啟動子、操縱元件(operator)以及一定距離外的調(diào)節(jié)基因。操縱元件是一段能被特異的阻遏蛋白(repressor)識別并結合的DNA序列，與啟動子序列毗鄰甚至重疊。阻遏蛋白與操縱子結合后，阻斷RNA聚合酶與啟動子結合或阻礙RNA聚合酶沿DNA向前移動，在轉錄水平上抑制基因表達。許多原核細胞基因操縱子中還有一段獨特的DNA序列，與激活蛋白(activator)結合后增強RNA聚合酶活性，在轉錄水平上調(diào)基因表達。調(diào)節(jié)基因編碼能與操縱序列結合的調(diào)控蛋白(modulin)，可分為特異因子、阻遏蛋白和激活蛋白三類，其中特異因子決定RNA聚合酶對一個或一套啟動子序列的特異性識別和結合能力。

任何生物體必然與其生存環(huán)境發(fā)生相互聯(lián)系并受之影響，由信號傳導系統(tǒng)(signaling system)感受外界信號并作出應答，其中跨膜感受器(sensor)蛋白激酶接受環(huán)境分子信號并向胞內(nèi)傳遞，最終通過TF調(diào)控相關基因表達來應對環(huán)境變化。與真核細胞比較，細菌等原核細胞信號傳導系統(tǒng)相對簡單，一般由兩類分工明確的蛋白組成，故稱之二元信號傳導系統(tǒng)(two-component signaling system，TCSS)：①跨膜傳感器蛋白(sensor protein，SP)：多為組氨酸激酶，少數(shù)為絲氨酸/蘇氨酸激酶；②胞漿內(nèi)應答調(diào)節(jié)蛋白(response regulator protein，RRP)，通常被跨膜傳感激酶磷酸化后激活，具有類似真核細胞TF功能，通過調(diào)節(jié)靶基因表達水平對環(huán)境信號進行適應性應答。例如，金黃色葡萄球菌(Staphylococcusaureus)ArlRS是調(diào)控許多毒力基因表達的TCSS，ArlS為SP、ArlR為RRP，ArlR上調(diào)sdrC/D/rE、tcaB和ssaA等毒力基因表達，但下調(diào)lukD/E、phlC和hlgC毒素基因表達；大腸埃希菌(Escherichiacoli)EnvZ/OmpR 是環(huán)境滲透壓TCSS，EnvZ為SP、OmpR為RRP，OmpR可分別與外膜孔蛋白OmpF和OmpC編碼基因啟動子區(qū)結合，低滲時OmpF表達上調(diào)、OmpC表達下調(diào)，高滲時OmpF和OmpC表達水平相反。

2 真核或原核細胞microRNA產(chǎn)生及特性

microRNA首先發(fā)現(xiàn)于秀麗隱桿線蟲(Caenorhabditiselegans)，此后發(fā)現(xiàn)真核或原核細胞均存在大量各種microRNA[12-13]。真核或原核細胞microRNA產(chǎn)生過程、分子大小與結構以及作用機制均存在一定差異。

2.1 真核細胞microRNA產(chǎn)生及特性[14-16]在RNA聚合酶的作用下，真核細胞microRNA編碼基因轉錄產(chǎn)生pri-microRNA，隨后Drosha 酶將pri-microRNA剪切成pre-microRNA，然后Ran-GTP 和 Exportin-5蛋白將pre-microRNA從細胞核運送到細胞質(zhì)，再經(jīng)胞漿Dicer核酸酶剪切成通常為21～23 nt左右成熟的單鏈小RNA(microRNA)。胞漿內(nèi)RNA誘導沉默復合體(RNA-induce silencing complex，RISC)可識別microRNA并將其遞呈至靶mRNA，大多數(shù)microRNA與靶mRNA的3’端非翻譯區(qū)(untranslated region，UTR)序列互補，抑制該mRNA翻譯或引起mRNA降解。動物約有1/3基因受到microRNA調(diào)控。

2.2 原核細胞microRNA產(chǎn)生及特性[17-20]原核細胞microRNA長度為50～400 nt，轉錄后一般不經(jīng)過加工即有活性。原核細胞microRNA起始一端折疊成莖環(huán)結構，轉錄終止于一個Rho不依賴的轉錄終止子。莖環(huán)結構具有穩(wěn)定microRNA的作用，使大多數(shù)microRNA穩(wěn)定性明顯大于mRNA。與真核細胞microRNA不同，原核細胞microRNA多與靶mRNA的5′端序列互補配對，且堿基互補配對方式也有所不同，與靶mRNA結合的microRNA隨靶mRNA一起降解。

3 真核或原核細胞microRNA作用機制

microRNA屬于反式作用因子，其主要作用是抑制靶mRNA翻譯或引起靶mRNA降解，在轉錄后水平下調(diào)基因表達，一種microRNA可調(diào)控多種mRNA，多種microRNA也可協(xié)同調(diào)控同一mRNA，甚至還能與TF經(jīng)前饋環(huán)(feed-forward loops，F(xiàn)FLs)協(xié)同調(diào)節(jié)同一基因的表達[20-22]。

3.1 真核細胞microRNA作用機制[21-24]真核細胞microRNA抑制基因表達機制：①抑制mRNA翻譯：常見于microRNA與靶mRNA互補配對程度較低者；②引起靶mRNA降解：常見于microRNA與靶mRNA互補配對程度較高者。microRNA與靶mRNA不完全互補時，其結合位點通常位于靶mRNA的3′端非翻譯區(qū)，可通過影響靶mRNA穩(wěn)定性、干擾靶mRNA與核糖體結合等方式抑制mRNA翻譯。microRNA與靶mRNA完全互補時，其結合位點通常位于靶mRNA編碼區(qū)(encoding region，ER)或開放閱讀框(open reading frame，ORF)中，與靶位點結合后引起靶mRNA的降解。植物microRNA大多與靶mRNA互補配對程度較高，動物microRNA大多與靶mRNA互補配對程度較低。

3.2 原核細胞microRNA作用機制[25-31]原核細胞microRNA可通過與靶mRNA堿基互補配對、與某些蛋白相互作用、RNA伴侶蛋白Hfq連接等方式在轉錄后水平調(diào)控基因表達。

3.2.1 microRNA-mRNA堿基互補配對 原核細胞 microRNA與靶mRNA堿基互補配可抑制或促進靶mRNA翻譯。多數(shù)細菌microRNA通過堿基不完全互補配對與靶mRNA的5′端核糖體結合位點(ribosome binding site，RBS)結合、導致mRNA的穩(wěn)定性降低或與5′端第5個密碼子結合，從而抑制mRNA翻譯。少數(shù)細菌microRNA結合于靶mRNA的3′端而使mRNA穩(wěn)定性增強，或結合于靶mRNA莖環(huán)結構使之打開，從而起促進mRNA翻譯的作用。

3.2.2 microRNA-蛋白相互作用[32-33]原核細胞microRNA與某些胞內(nèi)蛋白相互作用后可在轉錄后水平上調(diào)或下調(diào)靶基因表達。例如，大腸埃希菌、枯草芽胞桿菌(Bacillussubtilis)和惡臭假單胞菌(Pseudomonasputida)一些microRNA與蛋白結合后模擬核酸底物而抑制靶mRNA翻譯。此外還發(fā)現(xiàn)，大腸埃希菌RNA結合蛋白CsrA能與靶mRNA中RBS結合，阻斷該mRNA與核糖體的結合，從而抑制mRNA翻譯；CsrB或CsrC RNA可與CsrA蛋白結合，使CsrA蛋白不能與靶mRNA結合，從而發(fā)揮促進靶mRNA翻譯的作用。

3.2.3 RNA伴侶蛋白Hfq 多數(shù)原核細胞microRNA需RNA伴侶蛋白Hfq來增強其與靶mRNA的親和力以及對核酸酶的抵抗力。例如，大腸埃希菌Hfq以六聚體形式分別與microRNA及其靶mRNA結合，通過影響microRNA二級結構或改變microRNA與靶mRNA的局部濃度，從而提高microRNA對靶mRNA抑制作用甚至引起靶mRNA降解，該結合過程中microRNA的polyU尾和mRNA的U富集序列對Hfq連接功能至關重要[33-34]。

4 原核細胞microRNA-mRNA相互作用位點

細菌等原核細胞mRNA翻譯起始時需一個與mRNA結合的核糖體30S亞基、fMET-tRNAfMet和起始因子組成的起始復合物。位于mRNA起始密碼子上游富含嘌呤的SD序列(Shine-Dalgarno sequence)在mRNA捕獲核糖體30S亞基中起關鍵作用，該序列與16S核糖體RNA 3′端反義SD序列結合，促進mRNA翻譯[35-39]。細菌microRNA大多為反義RNA，作用于正義靶mRNA。細菌等原核細胞microRNA通常與靶mRNA 5′-UTR結合，抑制靶mRNA翻譯[38-39]。

4.1 microRNA-mRNA結合時mRNA的作用位點[38-41]細菌等原核細胞microRNA可與靶mRNA的SD序列堿基互補配對，使SD序列不能與核糖體30S亞基結合。有研究發(fā)現(xiàn)，大腸埃希菌和沙門菌microRNA與靶mRNA堿基互補配對位點位于mRNA RBS或其附近，若堿基互補配對位點超出起始密碼子上游70 或下游15 nt，microRNA抑制作用明顯減弱；此外，靶mRNA SD序列和起始密碼子未被結合時microRNA才能發(fā)揮作用。

4.2 microRNA-mRNA結合時microRNA的作用位點[41-42]腸道菌群microRNA具有如下模塊化特征：①具有富含U的3′端區(qū)域：促進不依賴Rho因子的轉錄終止并保護microRNA免受3′核酸外切酶的降解；②具有與Hfq蛋白結合的區(qū)域：通過與Hfq蛋白的結合來提高microRNA穩(wěn)定性；③具有與靶mRNA結合的區(qū)域：該區(qū)域序列非常保守，含有與靶mRNA結合的種子序列(seed sequence，SS)。目前發(fā)現(xiàn)，細菌microRNA均含有SS且位于microRNA的5′端，不同細菌microRNA的SS長度雖有差異，但通常為6～12個核苷酸。

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Advance in research of characteristics and action mechanism of microRNAs from prokaryotes

ZHANG Xin-wei1,3,HUANG Yan-ying1,3,YAN Jie2,SUN Ai-hua3

(1.SchoolofLaboratoryMedicine,WenzhouMedicalUniversity,Wenzhou325035,China; 2.DepartmentofMedicalMicrobiologyandParasitology,SchoolofMedicine,ZhejiangUniversity,Hangzhou310058,China; 3.FacultyofBasicMedicine,HangzhouMedicalCollege,Hangzhou310053,China)

microRNAs is a group of small non-coding RNAs that play a negative regulation role in expression of target genes at post-transcriptional level by inhibition or degradation of target mRNAs after combination of the seed sequence (SS) in microRNAs with the SS-binding sequences usually located at 5′ ends of target mRNAs. microRNAs was firstly found inCaenorhabditiselegans. Subsequently,many different microRNAs in eukaryocytes were revealed. In eukaryocytes,microRNA precursors are transcribed at first and then become functional microRNAs with 21-23 nt in size after splice. Most of eukaryocytic microRNAs combime with the sequences at 3′ end of target mRNAs that cause the translation inhibition or degradation of the mRNAs. In the recent years,many different prokaryocytes,such as bacteria,have been confirmed to possess microRNAs. However,the microRNAs in prokaryotes such as bacteria are 50-400 nt in size and have the biological activity without splice. Moreover,the characteristics,action sites and mechanisms of the prokaryotic microRNAs have some certain diversity compared to the eukaryotic microRNAs. Our review briefly introduce the major regulation mechanisms of gene expression as well as the general characteristics of microRNAs and their regulation mechanisms of gene expression in prokaryocytes and eukaryocytes,which will provide a basis for further and profound study on the gene expression regulation and pathogenic mechanisms of prokaryotic microbial pathogens.

prokaryotes; gene expression; regulation; microRNA; action mechanism

10.3969/j.issn.1002-2694.2017.05.012

國家自然科學基金(81271893)；浙江省衛(wèi)生高層次創(chuàng)新人才培養(yǎng)工程項目(2012-241)

孫愛華，sunah123@126.com

1.溫州醫(yī)科大學檢驗醫(yī)學院，溫州 325035； 2.浙江大學醫(yī)學院病原生物學系，杭州 310058； 3.杭州醫(yī)學院基礎醫(yī)學部，杭州 310053

R394.8

A

1002-2694(2017)05-0449-05

2016-11-11 編輯：王曉歡