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microRNA在结核分枝杆菌抗细胞自噬作用中的研究进展

  • 张益源1

    机 构：潍坊医学院临床医学院，潍坊 261053

    ×
  • 伊正君2

    机 构：潍坊医学院医学检验学系，潍坊 261053

    ×
  • 付玉荣1

    机 构：潍坊医学院临床医学院，潍坊 261053

    ×
1. 潍坊医学院临床医学院，潍坊 261053； 2. 潍坊医学院医学检验学系，潍坊 261053

中图分类号: Q5,Q93 DOI

DOI:10.16476/j.pibb.2018.0133

None

1. ； 2.

CLC: Q5,Q93 DOI

DOI:10.16476/j.pibb.2018.0133

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目录 contents

    摘要

    结核分枝杆菌（Mycobacteria tuberculosis，MTB）是结核病的致病菌，其感染机体后能在细胞内长期生存并在合适的条件下引发疾病. 非氧依赖性杀伤是巨噬细胞清除MTB的重要途径，主要表现为细胞内吞体和溶酶体融合，利用细胞自噬作用清除内部细菌. 相应的，MTB可利用多种方式顽强抵抗细胞自噬作用，与细胞共存从而逃避宿主免疫杀伤作用. MicroRNA（miRNA）是一种内源性非编码单链小RNA分子，其能在转录后水平沉默相关基因表达，是介导MTB与炎性细胞许多反应的重要分子. 近期研究发现，MTB能够通过诱导巨噬细胞特异表达一些miRNA分子并靶向自噬相关基因，阻碍自噬发生、发展，从而实现MTB的抗细胞自噬作用. 本文就miRNA在MTB抗细胞自噬中的作用及机制的研究进展作一综述.

    Abstract

    Mycobacteria tuberculosis (MTB) is the pathogen responsible for tuberculosis. It can exist in the infected-macrophages for a long time and trigger the disease when the appropriate conditions arise. The primary way to kill intracellular bacteria is via the oxygen-independent route. In this route, macrophages mainly rid themselves of parasites by autophagy where autophagosomes and lysosomes are fused into autophagolysosomes. However, MTB can resist to autophagy and avoid being killed by the immune system of host cells in several ways, thereby co-existing with the host. MicroRNAs (miRNA) are endogenous non-coding single-chain RNA molecules that can silence related genes expression in a post-transcriptional manner. They are crucial molecules for mediating inflammatory reactions between MTB and inflammatory cells. Recent studies found that MTB can induce the expression of certain specific miRNAs in macrophages and target genes related to autophagy and therefore inhibit triggering and progression of autophagy. This mechanism confers resistance to autophagy. The present review summarizes the role of miRNA in the resistance to autophagy by MTB.

    中国是全球结核病高负担国家，结核病是一种传染性极强的疾病，对个人和社会都能造成严重危害. 结核病的致病菌结核分枝杆菌（Mycobacteria tuberculosis,MTB）抵抗力顽强且难以被机体免疫清除，在人体内长期潜伏并能在人群中广泛传播，深入研究其致病原理和抵抗机制对于结核病的诊断、治疗和预后均有重要意义. 巨噬细胞能通过非特异性免疫应答，即氧依赖性杀伤作用和非氧依赖性杀伤作用消灭病原体，后者主要指细胞通过内吞病原体后形成自噬体并与溶酶体融合成自噬溶酶体，在溶酶体内的酸性环境及水解酶作用下消灭病原体，是非特异性免疫清除病原体的主要形式. 前期研究发现，MTB可以通过多种方式调控宿主细胞，使自身抵抗细胞免疫清除过程并逃避细胞免疫监视，如抵抗细胞自噬、抑制相关代谢反应、促进脂质体形成等多种方式[1]. miRNA沉默是转录后调控细胞基因表达的重要方式，近几年关于miRNA介导的MTB与细胞相互作用的研究不断增多，使得MTB调控宿主细胞相关反应的分子通路开始清楚[2]. miRNA介导的抗自噬作用是其影响结核分枝杆菌在细胞内长期生存的重要机制. 本文总结了当前有关miRNA介导MTB抗细胞自噬作用的研究进展，深入阐述了细胞内MTB能通过诱导多种miRNA并凭借其沉默自噬相关基因表达，从而实现其抵抗细胞自噬作用的生理过程，为理解MTB顽强的抵抗力和生存力提供新思路，并为临床诊断标志物选取、药物治疗靶点和预后指标选择提供新的选项.

  • 1 miRNA与自噬作用

    1

  • 1.1 miRNA

    1.1

    miRNA是长度约为22个核苷酸片段的单链非编码微小RNA，其在细胞内能通过形成RNA沉默复合体等方式与某些基因转录的mRNA的3’UTR碱基互补配对结合，阻止mRNA翻译并将其降解，在转录后水平调控相关基因的表达[3,4]. miRNA表达异常会导致某些疾病，或者某些疾病发生后miRNA表达显著变化，因此miRNA在疾病的诊断、治疗及预后均有潜在的临床价值[2]. 最近研究发现，miRNA在结核病的发生、发展中同样起到重要作用，结核发生时的细胞通信、细胞凋亡、细胞坏死等多种炎性反应过程均与自噬有密切联系，其中miRNA在自噬过程中的作用最为突出，相关研究也较为深入.

  • 1.2 自噬作用

    1.2

    自噬作用是指细胞在自噬相关基因的调控下利用溶酶体降解自身受损的细胞器和大分子物质的过程，巨噬细胞也能将自身吞噬体与溶酶体融合从而降解如病原体等吞噬的内容物[5]. 自噬作用消灭MTB是非特异性免疫的重要途径，MTB对细胞自噬也具有一定抵抗能力. MTB抵抗自噬的能力与其毒力密切相关，卡介苗（Bacillus Calmette-Guérin，BCG）、MTB弱毒株H37Ra抗自噬的能力较弱而MTB强毒株H37Rv抗自噬能力较强. H37Rv具有表达ESAT-6的基因序列RD1，有研究发现H37Rv的早期分泌抗原ESAT-6作用于mTOR（mammalian target of rapamycin）可起到抗自噬作用，转染ESAT-6（early secreted antigen 6）将显著增强BCG在巨噬细胞内的存活力而免于自噬[6]. 自噬相关基因是指能表达参与细胞内自噬过程的相关蛋白质的一系列基因，其表达程度受miRNA的调节. 一般来说，MTB感染细胞后，其自身相关蛋白质能够通过多种途径作用于宿主细胞，从而上调细胞内能靶向自噬相关基因的miRNA或是下调能靶向自噬负相关基因的miRNA，使多种自噬基因表达被抑制，最终阻止自噬作用过程发生[7]. miRNA介导抗自噬作用导致巨噬细胞无法有效清除MTB，使MTB与细胞共存并在细胞的保护下逃避细胞外免疫杀伤作用，这可能是活动性肺结核患者体内MTB长期潜伏及活动性肺结核患者肺部炎症迁延不愈的重要原因.

  • 2 MTB诱导的miRNA调控细胞自噬

    2

    细胞自噬与miRNA调控均是目前的研究热点，而能够调控细胞自噬作用的miRNA及其相应调控机制的研究也不断增多. 最近很多研究发现，巨噬细胞内MTB诱导的miRNA在细胞自噬过程的调控中起到重要作用，大部分 miRNA（miR-20a、miR-23a-5p、miR-30a、miR-33、miR-106b-5p、miR-3619b-5p、miR-125a-3p、 miR-144）的功能为抑制细胞自噬作用，显著增强MTB在细胞内存活的能力，有的miRNA (miR-26a)能够促进细胞自噬的作用，此外个别miRNA（miR-17-5p、miR-155）在不同的感染条件下具有促进自噬和抑制自噬的双重作用，机制较为复杂，现将目前这些miRNA研究的现状详细介绍如下.

  • 2.1 miRNA抑制细胞自噬

    2.1

  • 2.1.1 miR-20a抑制细胞自噬

    2.1.1

    miR-20a对于自噬基因调节作用在其他领域已有多篇文献报道，他可靶向ATG16L1（autophagy related 16-like 1）影响破骨细胞分化[8]，或靶向ATG10（autophagy related 10）抑制软骨细胞自噬[9]，或靶向BECN1及ATG16L1抑制自噬进而促进乳腺肿瘤发生[10]. Guo等[11]研究发现miR-20a可以通过靶向ATG7、ATG16L1抑制自噬从而增强BCG在巨噬细胞RAW264.7内的存活能力. ATG7（autophagy related 7）和ATG16L1是自噬形成过程的关键基因，他们参与初期自噬体膜的形成，促进LC3（autophagy marker light chain 3）的转化及自噬作用发生[12]. 实验中BCG感染细胞后miR-20a表达显著上调，ATG7、ATG16L1、LC3含量均显著降低，自噬作用明显减弱. 上述研究表明miR-20a能够调控自噬过程中多个自噬相关基因表达，这有助于更好地理解miRNA对结核病发生、发展的影响.

  • 2.1.2 miR-23a-5p抑制细胞自噬

    2.1.2

    Gu等[13]研究发现，miR-23a-5p可以靶向TLR2，通过TLR2/MyD88/NF-κB通路抑制细胞自噬作用，增强MTB在巨噬细胞内的存活率，其在感染MTB的RAW264.7、BMDMs中表达显著上调，并具有时间和剂量依赖性. TLR2（Toll-like receptor 2）有识别监测病原体的功能，MyD88（myeloid differentiation primary response 88）及NF-κB（nuclear factor kappa-light-chain-enhancer of activated B cells）是重要的炎症及免疫调节因子，当他们被沉默抑制后，对MTB杀伤能力下降，自噬作用减弱，MTB在细胞内得以生存[14]. Gu等认为miR-23a-5p是一个潜在的结核病治疗靶点，通过对其表达的抑制，能够逆转细胞感染状态及疾病的发生发展.

  • 2.1.3 miR-30a抑制细胞自噬

    2.1.3

    miR-30a在多个领域均有参与自噬基因调控的报道，靶向BECN1抑制自噬作用可以减弱胃癌细胞的多重耐药性[15]，还可抑制内皮细胞自噬促进动脉粥样硬化发展[16]. Chen等[17]发现，MTB感染的THP-1细胞内miR-30a表达上调，其能直接靶向BECN1抑制自噬过程从而帮助MTB免疫逃避，增强MTB抗自噬的能力及存活能力；临床试验中还发现，miR-30a在正常人、涂片阴性及涂片阳性活动性肺结核患者的肺泡巨噬细胞内表达量依次递增，肺结核患者治疗后比治疗前的表达量显著降低，这提示miR-30a是潜在的肺结核诊断鉴别生物分子及反应疾病预后效果的评价指标. Wu等[18]发现，MTB感染的THP-1细胞内miR-30a、miR-30e表达显著上调，miR-30a直接靶向MyD88且miR-30a能够抑制人巨噬细胞内TLR2、TLR4（Toll-like receptor 4）、MyD88、TNF-α（tumor necrosis factor alpha）、IL-6、IL-8的表达, 因此miR-30a在细胞自噬及相关炎性调控中具有非常重要的作用.

  • 2.1.4 miR-33抑制细胞自噬

    2.1.4

    Ouimet等[19]发现MTB可以诱导miR-33及miR-33*表达、抑制自噬作用、溶酶体生成、脂质体氧化等多种生物学作用，增强其在巨噬细胞内活力. 研究证实，miR-33能够靶向调控ATG5（autophagy related 5）、ATG12（autophagy related 12）、LC3B、LAMP1（lysosomal-associated membrane protein 1）等自噬基因以及FOXO3（forkhead box O3）、TFEB（transcription factor EB）等转录因子的表达，多重抑制自噬过程，破坏线粒体对脂质体的氧化，增加细胞内为MTB提供营养的脂质体的数量. 抑制miR-33表达后发现MTB存活力下降，细胞对MTB的清除能力显著增强. MTB在细胞内能持续生存免于自噬，还有细胞提供丰富的营养来源，因此该通路的发现有助于更好地理解结核病的MTB致病机制与免疫逃避作用.

  • 2.1.5 miR-106b-5p和miR-3619b-5p抑制细胞自噬

    2.1.5

    Pires等[20]发现，MTB感染的巨噬细胞内miR-106b-5p能够直接靶向溶酶体半胱氨酸蛋白水解酶CTSS（cathepsin S）基因，miR-106b-5p在细胞内表达显著上调，细胞内自噬过程减弱， MTB在细胞内的存活力增强. Pires等认为CTSS是一种在内吞泡和溶酶体内具有广泛pH适应环境的蛋白水解酶，通过miRNA将其沉默，避免MTB在囊泡中与水解酶的接触，可以使MTB在囊泡中持续生存. 但Pawar等[21]发现miR-3619-5p在BCG感染的THP-1细胞中表达下调，CTSS表达上调，BCG存活力因此下降，而转染miR-3619后BCG生存力增强. Pawar等认为，表达上调CTSS后清除MTB及抗原呈递作用增强，CTSS的抑制则会有相反的效果，即细胞对病原体的固有免疫将会减弱. 因此，miR-106b和miR-3619b均能通过沉默CTSS抑制自噬效应，有利于MTB在细胞内的生存.

  • 2.1.6 miR-125a-3p抑制细胞自噬

    2.1.6

    Kim等[22]发现MTB感染的巨噬细胞BMDMs和RAW264.7内的miR-125a-3p均显著上调，且具有明显的时间和剂量依赖性. miR-125a能通过靶向自噬基因UVRAG（ultraviolet radiation resistance-associated gene）抑制细胞自噬. UVRAG是巨噬细胞自噬体形成和自噬过程的必要基因，其能增强Rab7活性，促进自噬体和溶酶体融合[23]，UVRAG表达抑制有助于MTB在细胞内存活. 此外过表达miR-125a或是沉默UVRAG都将会减弱巨噬细胞对其内部MTB的抗菌反应；AMPK（AMP-activated protein kinase）或雷帕霉素则能够抑制miR-125a表达，上调UVRAG从而加强自噬，MTB成功被细胞免疫清除，这一发现有助于为临床治疗提供依据.

  • 2.1.7 miR-144抑制细胞自噬

    2.1.7

    Kim等[24]发现MTB感染的巨噬细胞hMDMs内miR-144-5p表达显著上调，通过靶向3’UTR的自噬基因DRAM2（DNA damage regulated autophagy modulator 2），抑制自噬过程中自噬体的形成，实验抑制miR-144后发现出现相反效应. 此外，临床试验发现肺结核患者的外周血和肺组织内miR-144-5p显著上调，DRAM2显著下调，这表明该分子相关调控在临床层面也有重要意义. DRAM2与BECN1、UVRAG相互作用，其能置换抑制BECN1的RUBCN（RUN and cysteine rich domain containing Beclin 1 interacting protein）分子并增强Ptdlns3K（phosphatidylinositol 3 kinase）活性，从而推动自噬过程发展. 因此，miR-144-5p能够靶向DRAM2明显抑制细胞内自噬体的形成及细胞对MTB的抗菌反应. Guo等[25,26]发现，感染BCG的小鼠细胞RAW264.7和树突状细胞内的miR-144-3p表达均显著上调，其能靶向自噬基因ATG4a（autophagy related 4a）的3’UTR，ATG4a能促进LC3转换，抑制细胞内自噬体形成，增强细胞内BCG的存活力. 上述多项研究表明miR-144在结核病的诊断、治疗及预后检测过程中可能均有重要意义.

  • 2.2 miRNA促进细胞自噬

    2.2

    Sahu等[27]研究发现miR-26a可以靶向抑制KLF4（Kruppel like factor 4），而KLF4能够阻止MTB转运至自噬溶酶体过程，增强精氨酸酶活性，抑制诱导性一氧化氮合酶活性[28]. 此外miR-26a还可以靶向CREB（cAMP responsive element binding protein）-C/EBP β（CCAAT enhancer binding protein beta），后者能够使NO水平降低并抑制巨噬细胞M2型极化[29]. 实验发现，MTB感染的BMDMs、RAW264.7、hMDMs（human marrow derived macrophage）细胞内的miR-26a及其前体均显著下调，KLF4的表达量升高，细胞氧依赖性和非氧依赖性杀伤MTB的能力均相应减弱，CREB-C/EBP β表达升高，M2型巨噬细胞减少. 因此，miR-26a有利于细胞自噬MTB，增强巨噬细胞杀伤细菌能力，该机制的发现丰富了MTB诱导的miRNA对自噬调控的形式，有助于更好地理解结核病的发生发展机制.

  • 2.3 miRNA双向调控细胞自噬

    2.3

  • 2.3.1 miR-17-5p双向调控细胞自噬

    2.3.1

    Duan等[30]实验发现，RAW264.7细胞内miR-17-5p能通过靶向自噬基因ULK1（unc-51 like autophagy activating kinase 1）从而减弱细胞自噬BCG作用，增强BCG存活力. BCG感染实验结果显示，该miRNA早期在细胞中上调并有显著性差异，4 h后开始下调从而导致BCG被巨噬细胞吞噬消除，体现了其对细胞自噬的抑制作用. 但其后也有研究发现，miR-17-5p可以通过靶向MCL-1（myeloid cell leukemia-1）、STAT3（signal transducer and activator of transcription 3）调节自噬作用从而减弱MTB在RAW264.7、BMDMs（bone marrow derived macrophages）细胞中的存活力，因此在MTB感染的细胞中该分子表达下调[31]. 具体调控通路为miR-17—PKC δ /STAT3—MCL-1—BECN1，即miR-17-5p可以抑制PKC δ（protein kinase C delta type）表达，而PKC δ可以激活STAT3，STAT3进一步激活MCL-1，MCL-1负性调节BECN1，BECN1是推动细胞自噬发生的关键自噬基因，最终BECN1（autophagy related 6）的表达量上调而自噬作用增强. 此外miR-17-5p还可直接靶向STAT3及MCL-1，进一步加强其对自噬的促进作用. miR-17-5p在促进自噬与抑制自噬方面均有相关报道，也有表达未发生变化的报道[11]，机制较为复杂，其在患者体内的实际功能有待于进一步研究.

  • 2.3.2 miR-155双向调控细胞自噬

    2.3.2

    关于miR-155对MTB感染细胞后作用的研究最为全面，它具有抑制细胞凋亡及炎性反应等作用，上下游调控通路研究比较清楚[32,33]. Wang等[34]发现，感染H37Rv型MTB的小鼠肺组织内miR-155升高2.5倍，BCG感染的BMDMs细胞内miR-155表达上调，BCG和H37Ra感染的小鼠巨噬细胞RAW264.7中miR-155表达上调，且具有时间、剂量依赖性. 他们发现miR-155能够靶向负调控自噬的基因RHEB（Ras homolog enriched in brain），诱导促进细胞自噬过程，增强细胞清除MTB的抗菌反应能力. 但近期Etna等[35]最新发现，MTB感染的树突状细胞内miR-155、miR-146等miRNA表达上升，其中miR-155能够靶向ATG3（autophagy related 3），阻止自噬泡的形成以及自噬溶酶体的融合，有利于MTB存活，沉默miR-155后则出现相反效应，因此miR-155在一些通路中也具有抑制细胞自噬的作用. miR-155是当前MTB细胞内调控通路研究最为详细的明星miRNA分子，其能够靶向多个mRNA，介导各种炎性反应，目前对自噬作用调控的发现是其介导的较为显著的细胞内生物作用，这为临床药物靶点及诊断标志物的选择奠定基础.

    综上所述，miRNA在MTB抗自噬中所起到的作用总结于表1，通路示意图见图1.

    表1 microRNAs 及其在MTB抵抗细胞自噬作用中的功能

    Table 1 microRNAs and their functions on MTB resistance to cell autophagy

    miRNA表达菌株细胞源靶mRNA调控通路及相关分子功能发表年份
    miR-17-5p↑BCG小鼠ULK1miR-17/ULK1/BECN1抑制自噬2015
    miR-17-5p↓H37Rv小鼠、人PKC、MCL-1miR-17/PKC/ STAT3/MCL-1促进自噬2016
    miR-20a↑BCG小鼠ATG7、ATG16L1miR-20a/ATG7/ATG16L1 /LC3抑制自噬2017
    miR-23a-5p↑H37Rv小鼠TLR2miR-23a/TLR2/MyD88/NF-κB抑制自噬2017
    miR-26a↓H37Rv小鼠、人KLF4、C/EBPβmiR-26a/KLF4/MCL1、EBPβ促进自噬2017
    miR-30a↑H37Rv人BECN1miR-30a/BECN1抑制自噬2015
    miR-30a↑H37Rv人MyD88miR-30a/TLR2/MyD88抑制自噬2017
    miR-33↑H37Rv人ATG5、ATG12、LC3B、LAMP1miR-33/ATG5、ATG12、LC3B、LAMP1、FOXO3抑制自噬2016
    miR-3619-5p↓BCG人CTSSmiR-3619/CTSS抑制自噬2016
    miR-106b-5p↑H37Rv人CTSSmiR-106b/CTSS抑制自噬2017
    miR-125a-3p↑H37Rv小鼠UVRAGmiR-125a/UVRAG/Rab7抑制自噬2017

    miR-144-5p

    ↑

    		H37Rv、BCG、H37Ra

    人

    DRAM2

    		miR-144/DRAM2/BECN1、UVRAG、LAMP1、LAMP2

    抑制自噬

    2016
    miR-144-3p↑BCG小鼠ATG4amiR-144/ATG4a/LC3抑制自噬2017

    miR-155

    ↑

    		H37Rv、BCG、H37Ra

    小鼠

    RHEB

    miR-155/RHEB

    促进自噬

    2013
    miR-155↑H37Rv人ATG3miR-155/ATG3/LC3抑制自噬2018
    表1 microRNAs 及其在MTB抵抗细胞自噬作用中的功能

    注：↑或↓：实验中菌株感染细胞后miRNA表达变化情况

    图1 miRNA介导的MTB抗细胞自噬作用示意图

    图1 miRNA介导的MTB抗细胞自噬作用示意图

    Fig. 1 The schematic diagram about MTB resistance to the autophagy in macrophage by miRNA

  • 3 总结及前景

    3

  • 3.1 总结

    3.1

    在巨噬细胞中，与结核分枝杆菌相互作用有关的miRNA目前研究较多且较为清楚的是miR-144、miR155，他们无论是在肺结核患者血清还是在肺组织中表达均显著上调，且与治疗效果相关，细胞实验也证实其显著的表达差异[36,37]. 如上文所述，他们在自噬调控方面也均有一定作用，且机制较为复杂多样，但主要效应为靶向自噬相关基因，阻碍自噬过程从而抑制自噬MTB，导致MTB在细胞内持续生存，临床上则导致肺组织内巨噬细胞难以清除持续存在的MTB，病灶持续存在并使疾病进一步恶化. 自噬是巨噬细胞非氧依赖性杀伤MTB的重要方式，也是MTB在细胞内被清除的重要原因，BENC1、UVRAG、DRAM2、ULK1、ATG3、ATG4、ATG5、ATG7、ATG12、ATG16L1、LC3、LAMP1、LAMP2等自噬相关基因均参与自噬过程，任何一个自噬基因的沉默都会影响自噬形成. MTB感染细胞后调控相关转录因子如FOXO3、TFEB等表达，进而导致细胞内miRNA表达显著变化，如miR-17、miR-20、miR-23a、miR-26a、miR-30a、miR-33、miR-106b、miR-125a、miR-144、miR-155、miR-3619等，他们通过靶向沉默各种自噬相关基因，从而阻碍细胞内自噬过程的各个阶段，最终导致细胞自噬能力明显减弱，细胞内MTB生存力明显增强从而持续生存，难以被自噬溶酶体吞噬、清除.

  • 3.2 存在的问题及前景

    3.2

    目前结核病在中国的流行形势仍然较为严重，结核病的治疗仍然没有较好的疗法，这是因为结核病的致病机制还不清楚，因此结核病的研究需要深入, 深入挖掘MTB调控细胞反应的分子通路，才能有的放矢，精确调控相关分子以治疗结核病. MTB是胞内寄生菌，主要繁殖的宿主细胞是巨噬细胞，目前对于MTB如何能够在巨噬细胞内潜伏并长期生存的调控机制还不很清楚. 因巨噬细胞通过自噬溶酶体降解MTB是清除MTB的重要方式，因此MTB如何抵抗细胞自噬从而与细胞共存是目前的研究热点，目前研究已经深入到非编码RNA干扰自噬基因介导MTB抗自噬的领域. 其中miRNA是细胞内RNA调控自噬的最主要方式，但是对于文中所述miRNA何为核心调控分子仍不清楚，交联调控通路仍不清晰，是否还存在其他未发现的重要miRNA分子等问题还需要更深入研究，miRNA用于诊疗、预后指标的可靠性还需进一步临床实验验证. 若能开发出特异且高效地沉默、封闭某些miRNA组合的新型治疗药物，显著增强机体对MTB的自噬清除能力，对结核病的临床治疗有重要意义. 此外某些发挥显著生物效应的miRNA在患者血清检测中也有明显变化，某些miRNA（如miR-30a等）含量远高于正常人，而经过药物治疗康复后含量又明显下降，这提示miRNA作为潜在的新型生物诊断标志物在临床诊断和治疗预后也有重大意义[36].

    Advances of The Functions of MicroRNA in Mycobacteria tuberculosis Resistance to Autophagy*

    ZHANG Yi-Yuan1）， YI Zheng-Jun2）， FU Yu-Rong1）**

    （1)College Clinical Medicine, Weifang Medical University, Weifang 261053, China;

    2)Department of Clinical Laboratory, Weifang Medical University, Weifang 261053, China）

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  • 基本信息

    DOI:10.16476/j.pibb.2018.0133

    中图分类号: Q5,Q93 DOI

    引用信息

    张益源,伊正君,付玉荣.microRNA在结核分枝杆菌抗细胞自噬作用中的研究进展[J].生物化学与生物物理进展,2019,46(01):43-50.

    .[J].Progress in Biochemistry and Biophysics,2019,46(01):43-50.

    基金信息

    国家自然科学基金项目（81470001）与山东省自然科学基金项目（ZR2016HM09）资助.

    This work was supported by grants from The National Natural Science Foundation of China (81470001) and Natural Science Foundation of Shandong(ZR2016HM09).

    稿件历史

    纸刊出版 : 2019-01-20
    收稿日期 : 2018-04-29
    录用日期 : 2018-11-05

    • 张益源

    机 构：潍坊医学院临床医学院，潍坊 261053

    伊正君

    机 构：潍坊医学院医学检验学系，潍坊 261053

    付玉荣

    机 构：潍坊医学院临床医学院，潍坊 261053
    miRNA表达菌株细胞源靶mRNA调控通路及相关分子功能发表年份
    miR-17-5p↑BCG小鼠ULK1miR-17/ULK1/BECN1抑制自噬2015
    miR-17-5p↓H37Rv小鼠、人PKC、MCL-1miR-17/PKC/ STAT3/MCL-1促进自噬2016
    miR-20a↑BCG小鼠ATG7、ATG16L1miR-20a/ATG7/ATG16L1 /LC3抑制自噬2017
    miR-23a-5p↑H37Rv小鼠TLR2miR-23a/TLR2/MyD88/NF-κB抑制自噬2017
    miR-26a↓H37Rv小鼠、人KLF4、C/EBPβmiR-26a/KLF4/MCL1、EBPβ促进自噬2017
    miR-30a↑H37Rv人BECN1miR-30a/BECN1抑制自噬2015
    miR-30a↑H37Rv人MyD88miR-30a/TLR2/MyD88抑制自噬2017
    miR-33↑H37Rv人ATG5、ATG12、LC3B、LAMP1miR-33/ATG5、ATG12、LC3B、LAMP1、FOXO3抑制自噬2016
    miR-3619-5p↓BCG人CTSSmiR-3619/CTSS抑制自噬2016
    miR-106b-5p↑H37Rv人CTSSmiR-106b/CTSS抑制自噬2017
    miR-125a-3p↑H37Rv小鼠UVRAGmiR-125a/UVRAG/Rab7抑制自噬2017

    miR-144-5p

    ↑

    		H37Rv、BCG、H37Ra

    人

    DRAM2

    		miR-144/DRAM2/BECN1、UVRAG、LAMP1、LAMP2

    抑制自噬

    2016
    miR-144-3p↑BCG小鼠ATG4amiR-144/ATG4a/LC3抑制自噬2017

    miR-155

    ↑

    		H37Rv、BCG、H37Ra

    小鼠

    RHEB

    miR-155/RHEB

    促进自噬

    2013
    miR-155↑H37Rv人ATG3miR-155/ATG3/LC3抑制自噬2018
    html/pibbcn/20180133/alternativeImage/72ebfd1b-2bea-4c0c-a39c-27e89817c0db-F002.jpg

    表1 microRNAs 及其在MTB抵抗细胞自噬作用中的功能

    Table 1 microRNAs and their functions on MTB resistance to cell autophagy

    图1 miRNA介导的MTB抗细胞自噬作用示意图

    Fig. 1 The schematic diagram about MTB resistance to the autophagy in macrophage by miRNA

    image /

    ↑或↓：实验中菌株感染细胞后miRNA表达变化情况

    无注解

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