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夏洪丽, 程俊, 喻大鹏, 陈文捷, 鲁义善
鱼类肽聚糖识别蛋白的研究进展
生物技术通报, 2018, 34(8): 58-66

XIA Hong-li, CHENG Jun, YU Da-peng, CHEN Wen-jie, LU Yi-shan
Research Progress on Peptidoglycan Recognition Proteins in Fish
Biotechnology Bulletin, 2018, 34(8): 58-66

文章历史

收稿日期:2018-03-15

鱼类肽聚糖识别蛋白的研究进展
夏洪丽1,3, 程俊1,3, 喻大鹏1,3, 陈文捷1,3,4, 鲁义善1,2,3     
1. 广东海洋大学深圳研究院,深圳 518116;
2. 广东海洋大学水产学院,湛江 524003;
3. 广东省水生动物健康评估工程技术研究中心,深圳 518116;
4. 中国科学院水生生物研究所,武汉 430072
摘要:肽聚糖识别蛋白(Peptidoglycan recognition proteins,PGRPs)是一类高度保守的模式识别受体(Pattern recognition receptors,PRRs)家族,能够识别细菌细胞壁的主要成分肽聚糖,进而激活并调节机体的先天性免疫反应。目前已报道的鱼类PGRP共23种,根据氨基酸序列的不同,PGRPs主要分为3类,分别是短型、中型和长型PGRPs。尽管鱼类PGRPs在大小、结构域布局及亚细胞定位方面有一定差异,但其C端的PGRP结构域是高度保守的。鱼类PGRPs在不同组织中广泛表达,在不同细菌的刺激下,鱼类PGRPs在各免疫组织的表达量均明显改变,推测鱼类PGRPs参与了机体的免疫应答过程。此外,鱼类PGRPs在生理过程、胚胎发育的先天性免疫调节中也扮演了重要角色。目前有关鱼类PGRPs的功能研究主要集中在病原识别能力,酰胺酶活性、杀菌抑菌性和免疫调节机制四个方面,尽管已经取得了一定的进展,然而对其作用机制的研究还不够深入,未来需要进一步深入的研究。针对鱼类PGRPs的结构、表达及功能进行综述,旨在为今后深入研究鱼类PGRPs的功能及应用提供思路。
关键词鱼类    肽聚糖识别蛋白    细菌    先天性免疫    
Research Progress on Peptidoglycan Recognition Proteins in Fish
XIA Hong-li1,3, CHENG Jun1,3, YU Da-peng1,3, CHEN Wen-jie1,3,4, LU Yi-shan1,2,3     
1. Shenzhen Research Institute of Guangdong Ocean University, Shenzhen 518116;
2. Fisheries College, Guangdong Ocean University, Zhanjiang 524003;
3. Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen 518116;
4. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072
Abstract: Peptidoglycan recognition proteins(PGRPs)are a family of highly-conserved pattern recognition receptors(PRRs), they may recognize peptidoglycans, an essential component of bacterial cell wall, consequently activate and regulate innate immunes of a body. At present there are 23 reported fish PGRPs, and they were classified into three groups based on the length of the amino acid sequence, named short-PGRPs, intermediate-PGRPs and long-PGRPs. Its C-terminal PGRP domain is highly conserved although fish PGRPs have some differences in protein size, domain organization and subcellular localization. Fish PGRPs widely express in different tissues, its expression levels display notable changes in various immune tissues under the stimulation of different bacteria, thus we speculate that fish PGRPs are involved in the immune response. In addition, fish PGRPs also play a vital role in the physiological process and innate immune regulation of embryonic development. Currently, researches on the functions of fish PGRPs mainly focus on pathogen recognition, amidase activity, bactericidal ability and antimicrobial activity, as well as immune regulatory mechanisms; however, researches on the mechanisms of fish PGRPs remain swallow, and needs further deep researches. This paper reviews the structure, express and function of fish PGRPs, aiming at providing for further studying the function and application for PGRPs in fish.
Key words: fish    PGRP    bacteria    innate immunity    

近年来,我国水产养殖业发展迅速,养殖业面临的诸多问题也日益突出,尤其是病原感染引起的水产病害,给养殖业造成了巨大的经济损失。疾病的发生是由病原、宿主和环境三者相互作用的结果,其中宿主的免疫应答对抵御病原微生物的感染具有重要作用,因此研究鱼类免疫应答机制一直是学术界的热点,特别是在胚胎发育早期发挥关键作用的先天性免疫。肽聚糖识别蛋白(Peptidoglycan recognition proteins,PGRPs)作为一种重要的模式识别受体,在鱼类抵御病原侵染过程中扮演着十分重要的角色。目前有关鱼类PGRPs的研究已经取得了一定的进展,本文综述了鱼类PGRPs的结构、表达及其功能,旨在为鱼类先天性免疫的研究提供理论参考。

1 PGRPs的发现

肽聚糖识别蛋白(Eptidoglycan recognition proteins,PGRPs)是一类可识别肽聚糖(Peptidoglycan,PGN)的模式识别受体家族,最早发现于家蚕血淋巴中[1]。随后,在昆虫[2]、棘皮动物[3]和脊椎动物[4-5]中相继被发现。目前已报道的鱼类PGRP共23种(表 1)。根据氨基酸序列的不同,PGRPs主要分为3类:短型PGRPs(Short-PGRPs,PGRP-S)、中型PGRPs(Intermediate-PGRPs,PGRP-I)和长型PGRPs(Long-PGRPs,PGRP-L)[6]。果蝇PGRPs主要分为两类:一类是较短的转录产物,包括PGRP-SA、-SB1、-SB2、-SC1A、-SC1B、-SC2和-SD;另一类是较长的转录产物,包括PGRP-LAa、-LAb、-LAc、-LB、-LCa、-LCx、-LCy、-LD、-LE和-LF[5, 7]。哺乳动物PGRPs有不同的转录产物:PGRP-S、PGRP-Iα、PGRP-Iβ和PGRP-L,也称为PGLYRP-1、PGLYRP-2、PGLYRP-3和PGLYRP-4[3, 8]。迄今,在包括斑马鱼(Danio rerio)[9-11]、岩鱼(Sebastes schlegeli)[12]、美国红鱼(Sciaenops ocellatus)[13]、草鱼(Ctenopharyngodon idella)[14-16]、斑点叉尾鮰(Ictalurus punctatus)[17]、大黄鱼(Pseudosciaena crocea)[18]、黄颡鱼(Pelteobagrus fulvidraco)[19]、虹鳟(Oncorhynchus mykiss)[20-21]、大菱鲆(Scophthalmus maximus)[22]、半滑舌鳎(Cynoglossus semilaevis)[23]和尼罗罗非鱼(Oreochromis niloticus)[24]等鱼类中发现3类PGRPs,其中PGLYRP-2与哺乳类PGLYRP-2为同源物,而PGLYRP-5(也称为PGRP-SC)和PGLYRP-6则是鱼类所特有的[17]

表 1 11种硬骨鱼的肽聚糖识别蛋白
2 PGRPs的结构与表达

在结构上,所有PGRPs的C端通常包含至少一个高度保守的PGRP结构域,与噬菌体T7溶菌酶和细菌的Ⅱ型酰胺酶有一定的相似性,而PGRPs在N端的序列长度差异较大,在不同生物间并不保守[3]。人类PGRPs都含有信号肽结构,而信号肽是蛋白质经典分泌途径的关键结构;然而,斑马鱼PGRP2,PGRP5并不含信号肽结构,但斑马鱼PGRPs也均是分泌蛋白[5, 25-26],其机制尚不明确。尽管鱼类PGRPs在大小、结构域布局及亚细胞定位方面有一定差异,但其C端的PGRP结构域是高度保守的。哺乳动物PGRP结构域的空间构象是由位于中心的几个β片层和外围的3个α螺旋(α1-α3)组成[27]。研究表明,鱼类PGRPs也有类似的结构,而个别剪切体因某个氨基酸位点的缺失,导致结构上稍有不同[9, 16, 24]

PGRP结构域都含有高度保守的半胱氨酸位点,其形成的二硫键是赋予PGRPs功能活性和维持蛋白结构稳定所必须的重要结构[28]。研究表明,该结构域中的某半胱氨酸位点突变将使其丧失酰胺酶活性[29-31]。晶体结构显示,PGRP结构域构象的正面凹槽含有保守的Zn2+结合位点,由两个组氨酸、一个酪氨酸和一个半胱氨酸组成,是结合肽聚糖的活性中心;其另一面为PGRP特异,且不保守的疏水区域,不同于催化酰胺键水解反应的Ⅱ型酰胺酶结构[31-34]。研究表明,结合PGN的凹槽结构被破坏后,将使其无法识别PGN,从而失去酰胺酶活性[29-30]。通过多重序列比对发现,鱼类PGRPs基本也都含有4个Zn2+结合位点,如图 1所示。说明鱼类PGRPs与哺乳动物可能有类似的功能,但其作用机制是否也依赖于半胱氨酸残基还有待进一步研究。

图 1 鱼类肽聚糖识别蛋白的多序列比对结果 箭头:保守的Zn2+结合位点

鱼类PGRPs在不同器官/组织中广泛表达,但其表达组织和表达量都存在明显差异。与斑马鱼PGRP2类似,美国红鱼、大黄鱼和大菱鲆PGRP2在各组织中普遍存在,尤其在肝脏中表达量最高[9, 13, 18, 22]。岩鱼PGRP-L1在肠和脾脏中表达量较高;其次是鳃和皮肤等,而PGRP-L2仅在肝脏中表达[12]。实验表明,在不同细菌的刺激下,鱼类PGRPs在各免疫组织的表达量均明显改变。因此推测鱼类PGRPs参与了机体的免疫应答过程,且发挥效应的部位各不相同,如草鱼PGRP6a、PGRP6d通过鳃和皮肤发挥作用,而PGRP6b的效应部位是肠,脾脏和肝脏等[16]。鱼类PGRPs的广泛表达将有利于机体及时将体内感染的病原体清除。同时,在非免疫组织中的表达说明PGRPs在生理过程过可能也扮演着重要角色。此外,实验表明,鱼类PGRPs在胚胎发育早期阶段的先天性免疫中发挥着关键作用[18, 26]

3 PGRPs的进化

利用生物信息学软件Clustalx和MEGA5.0构建了N -J(Neighbor-joining)进化树,对来自人类、小鼠、原鸡、非洲爪蟾和斑马鱼等14个物种(表 2)的PGRPs的进化关系进行分析,结果表明,不同物种的PGRP-S和PGRP-L分别独立进化,即同种类型PGRPs聚为一支,而与本物种的其他类型PGRPs同源性相对较低,这与以往的报道高度一致[3, 35](图 2)。

表 2 14个物种的肽聚糖识别蛋白
图 2 PGRPs的系统进化树
4 PGRPs的功能 4.1 病原识别能力

PGN是几乎所有细菌细胞壁的主要成分,包括L-赖氨酸(Lys型)和二氨基庚二酸(Dap型)两种类型,Lys型PGN主要存在于革兰氏阳性菌中,而Dap型PGN是革兰氏阴性菌的主要组成成分[36]。当细菌或其他含PGN的外源物体侵染机体时,能被宿主PGRPs识别并与之结合,从而激发机体的免疫效应。人PGLYRP3结合PGN后,其PGRP结构域的构象随即发生改变,将目标物固定在凹槽内,提高结合过程的亲和力[34, 36-38]。研究表明,鱼类PGRPs能够结合Lys型和Dap型两种PGN[14-15, 26]。除了PGN以外,人和鼠PGRPs还能够结合脂膦壁酸(LTA),脂多糖(LPS)等聚合物,但对后两者的亲和力明显较低,但猪PGLYRP1对LTA和LPS有很强的亲和力[39-41]。根据文献报道,PGN、脂膦壁酸(Lipoteichoic acid,LTA)和Ploy I:C均能够诱导草鱼PGRP5和PGRP6的高表达[14-16]。说明草鱼PGRP5、PGRP6与哺乳动物PGRPs类似,能够识别不同的病原相关分子模式(Pathogen-associated molecular pattern,PAMPs),至于其相互作用的亲和力是否有差异,还有待进一步的研究。

4.2 酰胺酶活性

PGRPs能够水解细菌肽聚糖中N -乙酰胞壁酸与L-丙氨酸之间的酰胺键,将有活性肽聚糖的分子片段化,从而使其失去活性,达到清除细菌的目的[31, 42]。人PGLYRPs中,仅PGLYRP2具有酰胺酶活性[36]。研究表明,保守的Zn2+结合位点对于PGRPs发挥酰胺酶活性是必须的[33-34]。如图 2所示,鱼类PGRPs的C端含有保守的半胱氨酸残基,暗示其和人PGLYRP2一样,都具有酰胺酶活性。文献报道多种鱼类的PGRPs都具有酰胺酶活性,且呈Zn2+依赖性[11-15, 23-24],2012年,孙黎等克隆美国红鱼PGLYRP2和PGLYRP2-AD(酰胺酶结构域),分别进行原核表达,分离纯化重组蛋白,并进行枯草芽孢杆菌肽聚糖的水解实验,结果显示,PGLYRP2和PGLYRP2-AD都具有酰胺酶活性,水解肽聚糖[13]

4.3 杀菌、抑菌活性

当PGRP与微生物细胞壁成分结合后形成复合物,能够激活酚氧化酶,经过一系列反应,将含酚的化合物氧化成醌,转换成黑色素将微生物包裹来限制其感染[2]。哺乳动物PGRPs只有酰胺酶活性或者杀菌活性,与PGLYRP2不同,人PGLYRP-1,PGLYRP-3,PGLYRP-4在对应Cys530位点上是丝氨酸而非半胱氨酸,无法结合Zn2+,因此PGLYRP-1,PGLYRP-3,PGLYRP-4只有杀菌活性[30, 43-44]。后两者形成的异二聚体PGLYRP3:4也同样有高效的杀菌作用[44]。研究表明,鱼类PGRPs同一分子往往兼具酰胺酶和杀菌两种特性[12, 26]。除了酰胺酶活性以外,岩鱼PGRP-L1和PGRP-L2还具有广谱杀菌功能[12]。因此猜测PGRPs的杀菌机制与其自身的酰胺酶活性可能存在某种关联,但目前还没有相关的实验证实这一猜想。斑马鱼PGRPs不仅能有效杀灭革兰氏阳性菌,对革兰氏阴性菌也表现出不同程度的杀菌作用。然而,美国红鱼PGLYRP2只对革兰氏阳性菌有很强的杀灭作用[13]。鱼类PGRPs在抗菌免疫中表现各异,即使同一物种的不同PGRPs分子的作用也不尽相同,至于其作用机制还有待进一步研究。

4.4 免疫调节

PGRPs在免疫反应中发挥着重要作用,包括免疫调节过程[31, 42, 45]。除了识别病原体,PGRPs还通过调节机体免疫以便能够及时有效地清除入侵的病原体。研究表明,并非所有的PGRPs都有很强的杀菌作用。例如,半滑舌鳎PGRP-SC2并非是直接杀死细菌的效应物,而是通过提高细胞的吞噬能力来抑制机体内细菌的定植与传播[23]。与此类似,罗非鱼PGRP-SC2并未表现出明显的杀菌作用,却能显著降低靶器官内无乳链球菌的载量,说明其在抵抗无乳链球菌感染过程中扮演着重要角色[24]

起初认为PGRPs是一个简单的效应分子,随着研究的深入,发现昆虫PGRPs能够激活Toll或IMD信号传导通路或诱导蛋白水解级联反应,从而提高抗菌免疫反应[45]。研究表明,鱼类PGRPs不仅是典型的模式识别受体,还可介导细胞内的Toll、MAPK、JAK/STAT和NF-KB多条信号通路,从而调节下游免疫相关基因的表达。由于昆虫PGRPs的水解肽聚糖的酰胺酶活性,可以防止机体出现过度炎症反应,因此推测哺乳动物PGRPs也有抗炎效应[42, 46-47]。然而,与预期结果相反,实验表明哺乳动物PGLYRP2在PGN感染机体过程中发挥了促炎效应[48]。为探究鱼类PGRPs的功能,Jang等[20]通过构建酰胺酶失活突变体,发现虹鳟PGRP-L1能够抑制IL-1β和TNF-a等下游炎性因子的表达,说明虹鳟PGRP-L1发挥了抗炎功能,且该调节机制与其酰胺酶活性无关。此外,鱼类PGRPs能促进穿孔素、抗菌肽的分泌,从而在机体的抗菌免疫反应中发挥协同效应[16]

选择性剪切是单个基因剪切合成多功能信使RNA的过程,是真核生物中普遍存在的一种现象,会影响免疫系统中关键蛋白的结构和功能[49]。草鱼PGRP6的不同剪切体虽然都能抑制体内细菌的增长,但其作用机制也各不相同。PGRP6a,PGRP6b和PGRP6c能诱导铁调素和G-溶菌酶的表达,而草鱼PGRP6和PGRP6d却无此功能。另外,4个剪切体中只有PGRP6c能够影响穿孔素的分泌,说明在抑菌活性的基础上,草鱼PGRP6的不同剪切体还有功能特异性[16]

5 展望

PGRPs在机体先天性免疫过程中发挥着重要作用,目前有关鱼类PGRPs的研究已经取得了一定的进展,然而对其作用机制的研究还不够深入。PGRP-L的N端几乎占据整个分子的2/3,该段蛋白的结构差异较大的原因是什么,以及发挥的作用是怎样的;PGRPs的杀菌作用与酰胺酶活性是否存在一定的联系。以往的报道发现,PGRPs能够抵御真菌的感染,且软体动物PGRPs对寄生虫刺激也有一定的防御作用,那么鱼类PGRPs是否也有类似的功能。

免疫信号通路是一个十分复杂的网络。PGRPs作为分泌蛋白,却能显著抑制NF-kB活性,因此,推测细胞内可能存在某种表面受体来协助PGRP完成信号的转导,至于受体是什么又是如何发挥作用的,就不得而知了。研究表明,虹鳟PGRP-L1和核苷酸结合寡聚化结构域(Nucleotide-binding oligomerization domains,NODs)在抗菌免疫应答中存在相互依赖,并能够调节部分炎症因子的表达,但对IL-10的表达却没有任何影响[50]。那么PGRPs与其他免疫信号是否也有一定的关联;又是如何影响下游信号转导,以上问题都需要进一步的研究探索。

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