细胞处于不利环境或遇到有害刺激时产生的防御或适应性反应称为应激,应激反应发生在整体和细胞层面,其中后者称为细胞应激[1]。而内质网应激是细胞对抗应激环境的一种主要适应和自我保护机制,其反应的激烈程度决定着细胞重新建立内稳态还是激活死亡程序,参与调控机体由应激向健康或疾病的转变过程[2]。
葡萄糖调节蛋白94(glucose-regulated protein 94,GRP94)作为内质网分子伴侣,参与内质网蛋白的折叠、转运、分泌以及内质网相关蛋白的降解等生物学过程[3]。此外GRP94是内质网应激的标志蛋白,在细胞应激状态下对稳定内质网内环境至关重要。近年来,国内外学者对葡萄糖调节蛋白参与的信号通路进行了研究,发现GRP94可以通过内质网信号途径来调控细胞凋亡的发生[4-6]。但是,GRP94与内质网信号通路上下游关键因子如何发生作用来实现该生物学功能还不清楚。本文将从内质网应激、GRP94及其互作蛋白、GRP94调控细胞凋亡的机制及GRP94与肝疾病等几个方面进行综述。
1 内质网应激畜禽生产中,规模化、集约化程度越来越高,饲养空间受限、冷热环境不适、生产操作频繁等经常会导致畜禽产生应激反应,影响其健康状态和生产性能,给养殖业造成巨大的隐性损失[7-9]。同样,面对越来越激烈的竞争,人们的生存压力递增,常常使自身处于亚健康状态,呈现出类似于畜禽的应激反应症状[10]。据报道,内科初诊病例75%~90%与应激相关[11]。无论畜禽还是人类,广泛存在的应激反应最后都会导致细胞应激,影响细胞存活,其中内质网发生应激就是细胞应对应激环境的一种主要自我保护和适应机制。
内质网是一种重要的细胞器,在真核细胞中广泛存在,负责蛋白质合成、修饰与加工、折叠、组装和运输等。内质网功能正常运行对细胞的存活至关重要。细胞受到冷、热、辐射、化学毒素、缺氧等内外因素强烈刺激,引起其内质网囊腔内出现大量的未折叠蛋白和错误折叠蛋白聚积,当超出内质网处理能力时,细胞会激活未折叠蛋白反应(unfolded protein response,UPR)等信号途径,形成内质网应激(endoplasmic reticulum stress, ERS)[12]。研究指出,机体应激时,ERS可能是发生在细胞内的最早期反应,它能激活内质网伴侣蛋白等蛋白分子表达,以保护细胞、对抗应激、维持存活。但持续或过度的应激反应亦可能会影响内质网的结构和功能,激活炎症反应,进而引发一系列病理性反应,最终导致细胞凋亡,甚至死亡[13-15]。
2 GRP94及其互作蛋白葡萄糖调节蛋白94(GRP94)是细胞ERS的重要反应因子。GRP94又称为内质网蛋白99、HSP90B1(heat shock protein B1)、GP96(glycoprotein 96),是一种HSP90家族的分子伴侣,主要存在于内质网中,是内质网发生应激时的标志性蛋白[16]。当细胞出现ERS时,诱发UPR,GRP94参与纠正错误折叠蛋白,进而维持内质网内环境的稳定及钙稳态[17]。
GRP94作为分子伴侣,参与诸多蛋白的正确折叠和成熟分化, 有较多的互作蛋白。GRP94在内质网功能网络中起着关键作用,GRP94与其互作蛋白监控蛋白正确折叠,并及时消除错误折叠蛋白。研究发现,蛋白Hspa5、Dnajc3、Dnajc10、Eroll1I、Erp44、Hspd1和Npml均富集于内质网,与GRP94结合,以响应细胞ERS和UPR[18]。在ERS条件下,边缘带B和B1细胞特异性蛋白(marginal zone B and B1 cell-specific protein,MZB1)作为GRP94特有的底物分子伴侣,促进μ重链的生物合成,并使其与GRP94发生反应[19]。
细胞处于ERS状态时,GRP94上调通过与其互作蛋白胰岛素样生长因子(insulin like growth factor,IGF)的前体结合,加快IGF最终的成熟及分泌[20]。IGF在ERS下存在双向调节作用,一方面在细胞中,UPR通过GRP94的上调加快IGF的成熟和分泌,IGF通过触发抗凋亡的信号通路抑制细胞凋亡[21-22];另一方面IGF在ERS下快速成熟分化的同时促进肌醇需求酶1(inositol requiring enzyme1,IRE1)和PKR类似内质网激酶(PKR-like eukaryotic initiation factor 2α kinase,PERK)通路对UPR的响应[23]。因此,IGF与UPR之间存在一种环状的负反馈调节机制,而这一机制在ERS下的正负调节作用仍需要进一步的研究。此外,钙蛋白酶、促凋亡相关基因肿瘤蛋白53(tumor protein p53,P53)、低密度脂蛋白受体相关蛋白6(low-density lipoprotein receptor-related protein 6,LRP6)和Toll样受体4等也已证实与GRP94存在互作关系,并参与调控ERS下细胞凋亡的机制[24-27]。互作蛋白的研究是为了更深入了解GRP94在细胞ERS条件下的功能,并解释其互作蛋白参与细胞凋亡的作用机制,但GRP94及其互作蛋白参与细胞凋亡的机制仍需要深入探索。
3 GRP94对细胞凋亡的调控机制近年来,ERS诱导的细胞凋亡逐渐成为一种新的细胞凋亡途径。已发现,介导ERS的致死信号包括PERK诱导的C/EBP同源蛋白(C/EBP homology protein,CHOP)表达、半胱氨酸天冬氨酸水解酶12(cysteine aspartic acid specific protease 12,Caspase 12)的激活和IRE1诱导的c-Jun氨基末端激酶(c-JNN N-teminal kinase,JNK)信号通路激活[28-29]。ERS相关的UPR是一种非常精细的细胞适应性反应,主要由3个位于内质网膜上的IRE1、PERK和转录激活因子6(activating transcription factor 6,ATF6)介导的信号通路调控[12]。3条UPR信号通路的激活有助于降低细胞中蛋白合成,加快错误折叠蛋白降解及促进内质网分子伴侣蛋白的产生,最终缓解内质网蛋白折叠的压力[30-31]。适度的UPR可有效地保护细胞,但如果持续的ERS造成未折叠蛋白大量累积,超出了细胞可适应的范围,便会触发细胞凋亡[32]。近期研究提示,UPR 3条信号通路不同程度的激活可能是导致细胞凋亡的关键性因素[33-36]。在ERS长期存在的状况下,IRE1、ATF6两条通路的活性及产生的作用减弱,而PERK信号通路则可持续激活,从而促进细胞凋亡[37-38]。IRE1通过激活X盒结合蛋白1(X-box binding protein 1,XBP1)促进应激细胞存活[39]。
国内外学者对葡萄糖调节蛋白参与的信号通路进行了研究,发现GRP94可通过内质网信号途径来调控细胞凋亡的发生。作为ERS标志性蛋白,GRP94基因启动子中含有许多ERS反应元件,应激条件下,促使GRP94表达显著上调,提示细胞发生了ERS[40]。通过对文献的总结归纳发现,GRP94调控细胞凋亡可能有3种方式,但从文献数量和研究结论来看,GRP94主要起抑制细胞凋亡的作用。
3.1 GRP94抑制细胞凋亡当GRP94过表达时,不会促进细胞凋亡的发生,反而会阻碍凋亡效应分子的分泌[41];当干扰GRP94表达时,肝癌细胞增殖明显受到抑制,细胞死亡率显著增加[42],该结论在胰腺癌细胞中也得到了进一步验证[43];在一项多发性骨髓瘤研究中发现,分子伴侣GP96(即GRP94)通过活化信号通路,促进肿瘤细胞增殖,而通过选择性抑制剂WS13处理后,肿瘤细胞的增殖能力受到抑制,促进细胞凋亡的发生,表明GRP94抑制细胞凋亡[44]。通过相关文献总结发现, GRP94主要从4个方面发挥其抗凋亡作用:1) GRP94在ERS下过表达,充分发挥其Ca2+缓冲功能。ERS下会导致内质网大量Ca2+流失,激活B淋巴细胞瘤因子(B-cell lymphoma,Bcl),促使细胞凋亡。GRP94分子具有多个Ca2+结合位点,可结合16~28个Ca2+[45]。ERS下GRP94维持钙池稳定,减少Ca2+流出,进而保护细胞[24]。2) P53蛋白属于一种肿瘤抑制因子,已被证实在肝癌细胞中发挥着促进细胞凋亡的生物功能。GRP94在ERS下通过E3泛素连接酶-MDM2将其互作蛋白P53泛素化和降解,从而抑制细胞凋亡[25]。3) IGF信号通路在机体中的主要生物学功能是促进生长、分化和增殖等,并抑制细胞凋亡。GRP94与IGF前体结合促进IGF成熟,很大程度上控制IGF后续的生物效应[20]。4) GRP94具有抗氧化作用。在肌源性细胞的研究中发现,姜黄素通过促使GRP94过表达缓解了过氧化氢导致的细胞凋亡[46]。
但ERS程度过强或持续时间过长,导致GRP94抑制细胞凋亡的生物学功能失效。现将导致GRP94功能失效的机制进行总结:GRP94在ERS下过表达与多个Ca2+结合,形成微环境,而微环境内部Ca2+浓度过高,足以激活钙蛋白酶。GRP94的羧基末端位于内质网膜上,属于跨膜蛋白,胞质中的钙蛋白酶与GRP94亚群结合进而对GRP94进行裂解。裂解后的GRP94导致Ca2+流失,Ca2+一方面进入线粒体,破坏钙离子的代谢调控,另一方面激活caspase相关酶,加速细胞凋亡[47]。GRP94上游蛋白异戊烯半胱氨酸羧基甲基转移酶(isoprenylcysteine carboxyl methyltransferase,ICMT)受到抑制后,导致GRP94蛋白表达下降和等电点发生多重变化,GRP94出现再定位、聚积和降解,进而细胞出现凋亡[48]。采用RNAi技术外源性导入靶向GRP94的siRNA,直接抑制GRP94表达后也发现细胞凋亡比例明显增加,这可能与GRP94下调的原癌基因c(c-myc)、细胞周期素D1(cylinD1)、生存素(survivin)蛋白表达有关[49]。干扰GRP94表达后,细胞促凋亡效应可能由IRE1-JNK-Bcl2途径介导,IRE1通过肿瘤坏死受体相关因子2和凋亡信号调节激酶1结合,激活JNK信号通路,进而促使Bcl2过表达,导致细胞凋亡[50-51]。
3.2 GRP94促进细胞凋亡近期研究发现,在人心肌细胞中通过促进microRNA-150的表达抑制GRP94,有助于降低在低氧情况出现的细胞凋亡[52]。另有研究报道,低氧条件下GRP94与Toll样受体4(toll-like receptor 4,TLR4)结合,通过介导TRAF2/ASK1/JNK通路促使肾小管上皮细胞出现凋亡[27]。Wnt信号通路与细胞凋亡密切相关,其受体蛋白LRP6的成熟和细胞表面表达均与GRP94密切相关。GRP94与LRP6互作加快LRP6成熟,并促进其在细胞表面表达[53-54],而LRP6的表达又激活Caspase9,促使细胞凋亡的发生[26]。
3.3 GRP94促进和抑制双向调节细胞凋亡内质网内未折叠蛋白积聚时,GRP94可从正常状态下与跨膜蛋白IRE1、ATF6和PERK的结合状态分离出来,以应付UPR,并启动3条通路,从而介导不同的下游反应,即存在一个负反馈机制调控GRP94表达,从而降低和消除GRP94的活性,增加对错误折叠蛋白的稳定保护作用[55]。此外,如上所述,GRP94的Ca2+缓冲功能,在ERS程度较弱的情况下,通过避免Ca2+流入胞质,保护细胞,抑制凋亡;但ERS程度较强的情况下,GRP94裂解,Ca2+进入胞质,影响线粒体代谢功能及激活Caspase相关蛋白,反而加快了细胞凋亡。尽管这些研究进展初步揭示了GRP94与细胞凋亡存在着联系,但GRP94到底如何调控细胞凋亡还有待深入研究。
4 GRP94与肝疾病肝是畜禽和人体内最大的实质性器官,也是机体重要的代谢与解毒器官。肝细胞代谢功能活跃,拥有非常丰富的内质网,因此对于细胞内外因素的变化应激反应也很强烈。许多肝病,如肠外营养相关性肝病、非酒精性脂肪肝、纤维化肝病等的发病机制均与ERS有关[56-59]。而外界刺激因素不能及时排除,ERS通过IRE1凋亡通路持续诱发细胞凋亡,导致肝损伤[60-61]。GRP94作为ERS标志蛋白,发挥其分子伴侣生物活性,参与肝相关疾病的发生、发展。
4.1 GRP94表达与肝癌最近研究证实,GRP94在肝内稳态、脂肪变性和癌症发展中发挥重要作用。但GRP94在肝癌变发生过程中所起的作用仍存有争议。Chen等[62-63]发现,在小鼠肝中GRP94缺失, 细胞外信号调节激酶被选择性激活,肝细胞表面整合素丢失,细胞黏附及祖/干细胞的扩增,最终导致肿瘤发生,提示GRP94是维持肝内环境稳定和肿瘤发生重要的调节因子。这一结果与GRP94伴随着肿瘤发生并参与恶性演进的报道并不一致。Angel等[64]比较了正常肝组织、癌旁组织及肝癌组织中GRP94表达情况,发现GRP94的表达可能参与了肝癌的发生、发展。在二乙基亚硝胺诱发癌变的过程中,GRP94虽然有助于维持肝细胞的内稳态,但也加快肝癌变[20]。研究发现,GRP94可能通过Wnt/β连环蛋白信号通路诱导肝癌细胞的发生和发展,LRP6作为GRP94的互作蛋白,与Wnt分子结合,促进β连环蛋白积累,进而激活一系列基因,调控肝癌细胞的增殖、凋亡、迁移等[42]。此外,GRP94作为分子伴侣拥有诸多互作蛋白,其中糖蛋白A重复序列为主的跨膜蛋白(glycoprotein A repetitions predominant,GARP)、TLR、IGF及整合素亚基(α和β)等均参与了GRP94的致癌作用[65]。
4.2 GRP94表达与病毒性肝炎乙肝病毒(hepatitis B virus,HBV)和丙肝病毒(hepatitis C virus,HCV)导致肝出现急性或慢性炎症,当肝炎发展为肝硬化时,诱发肝癌的概率显著增加[66]。研究发现,GRP94是稳定和调控HBV RNA聚合酶的关键调控因子,HBV病人GRP94的高表达与其不良预后密切相关[67-68]。GRP94表达的升高伴随着HBV引起的整个病程进展,如慢性炎症、肝硬化及最终导致的肝癌[69]。研究发现,GRP94与HBV复制之间存在正反馈回路,其中HBV的x蛋白通过核因子κB(nuclear factor kappa-B,NF-κB)诱导GRP94表达,而GRP94的高表达反过来促进HBV的复制和生产[67]。HCV的糖基化蛋白E2诱发细胞ERS,并使GRP94表达上调。HCV利用GRP94及其他分子伴侣如GRP78来维持病毒蛋白的内稳态,以维持病毒的持续性感染,并抑制细胞蛋白的翻译。GRP94表达敲低后抑制E2的抗凋亡活性,表明E2可通过GRP94发挥其抗凋亡活性[70]。GRP94在HBV和HCV感染细胞及抗凋亡中起重要作用,而且与肝癌细胞的增殖、凋亡、迁移密切相关,因此,深入探究GRP94在肝发病机制中的作用,对肝病的防治具有重要的临床意义。
5 GRP94在畜禽方面的研究进展畜禽在应激条件下通常会通过激活热休克蛋白(heat shock protein,HSP)家族相关蛋白,以缓解应激造成的不良反应。其中,GRP94也称HSP90B1,是HSP90的亚型,在畜禽应激中起重要作用。引起畜禽应激反应的因素有很多,包括日粮因素、环境因素及病理因素等。有研究发现,肉鸡饲喂含有黄曲霉素B1的日粮,会通过内质网途径导致法氏囊和脾出现细胞凋亡,其中GRP94基因表达显著上调[71-72]。日粮中微量元素过高也会诱发ERS,如肉鸡日粮中镍含量过高,会使肉鸡肾中GRP94基因和蛋白均显著上调,并触发UPR通路[73]。畜禽在高温环境下也会出现ERS。持续慢性热应激对育肥猪肝蛋白组学变化的研究发现,在引起育肥猪肝发生ERS,GRP94蛋白和mRNA表达水平显著升高的同时,肝细胞凋亡率也显著增加[74]。Xu等[75]研究发现,在热应激下鸡脾中GRP78和GRP94蛋白表达显著上升。动物机体处于热应激会激活特异性应答反应,ERS被激活有可能与机体自我调节和适应有关。畜禽在泌乳期也会诱发ERS,并引起感染性疾病。母猪在泌乳期,肝和骨骼肌中GRP94及UPR相关指标的基因和蛋白表达显著上调,原因可能是母猪在泌乳期促炎症因子含量增加,诱发ERS,而ERS又会刺激细胞因子、活性氧等的产生,导致母猪分娩后出现感染性疾病。研究发现,通过限制母猪采食量,或是日粮中添加鱼油,可以缓解母猪的ERS和炎症反应[76-77]。另有研究发现,GRP94在牛乳腺发育阶段基因表达开始上调,且一直维持到泌乳期,表明GRP94合成受到乳腺发育和分化的调控,并在泌乳期促进乳蛋白的成熟[78]。
GRP94作为免疫调节因子,在疫苗研发中也有重要作用。GP96(GRP94),作为调制器,提高了猪繁殖与呼吸综合征病毒(porcine reproductive and respiratory syndrome,PRRS)亚单位疫苗的免疫原性,加强了固有免疫与适应性免疫[79]。GP96也可作为猪圆环病毒2型(porcine circovirus 2,PCV2)亚单位疫苗佐剂,提高疫苗对猪的免疫保护效果[80]。此外,GP96作为甲型流感病毒H1N1疫苗的佐剂,通过增加抗原特异性T细胞反应,发挥其交叉保护能力[81]。
6 问题及展望综上所述,内质网应激诱发的UPR信号通路与肝细胞凋亡密切相关,而GRP94作为内质网标志蛋白,在内质网应激条件下与内质网元件相互作用,参与肝细胞凋亡的活化。但要明确GRP94调控肝细胞凋亡的机制仍存在较大的难度,有许多关键问题需要考虑:1)GRP94调控肝细胞凋亡的生物学作用并不一致,亟需更为可靠的机制研究来阐明其确切的作用机理。2)GRP94作为分子伴侣,在内质网中与众多蛋白存在相互作用,筛选并验证出具有生物学意义的GRP94互作蛋白,对阐明GRP94的生物学作用更有帮助。3)ERS是细胞适应和自我保护机制,ERS程度过强或持续时间过久,诱发细胞凋亡。ERS程度的界定或划分仍有很大难度,GRP94被钙蛋白酶裂解程度或GRP94结合的Ca2+流失程度可否作为划分标准,但仍需深入思考。4)诸多肝疾病诱发的细胞凋亡与ERS有关,其中GRP94的高表达伴随着病情的发生、发展,并参与肝病诱发的细胞凋亡调控。发生肝疾病时细胞凋亡、ERS和GRP94相互关联,但明确的内在关联仍需开拓性研究。
研究某个蛋白的功能通过研究其互作蛋白也是一种重要的方式。GRP94作为分子伴侣,多与其他蛋白形成复合物一起发挥生物学作用。通过文献及数据库检索筛选GRP94互作蛋白,并采用敲低GRP94互作蛋白等分子生物学手段揭示ERS条件下GRP94及其互作蛋白调节肝细胞凋亡的作用机理,可望为畜牧上引起内质网应激的生产条件调控、临床上与内质网应激相关的肝病治疗提供新的科学依据。
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