2016, Vol. 36文章信息
- 陈娜子, 姜潮, 李校堃
- CHEN Na-zi, JIANG Chao, LI Xiao-kun
- 内质网应激与疾病
- Role of Endoplasmic Reticulum Stress in Diseases
- 中国生物工程杂志, 2016, 36(1): 76-85
- China Biotechnology, 2016, 36(1): 76-85
- http://dx.doi.org/10.13523/j.cb.20160111
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文章历史
- 收稿日期: 2015-08-17
- 修回日期: 2015-09-11
内质网(endoplasmic reticulum ,ER)是真核细胞内非常重要的多功能细胞器，在完成基本生理功能的同时，内质网凭借其庞大的膜结构成为协调信号转导的枢纽平台。内质网是脂类和固醇合成、维持Ca2+动态平衡、蛋白质合成与折叠及其翻译后修饰的场所[1, 2]，同时也参与脂质和类固醇代谢。内质网腔是一个独特的细胞区室，能进行Ca2+的活性转运;内质网腔是细胞内Ca2+浓度最高的区室。在正常生理条件下，Ca2+通过内质网膜上钙泵(SERCA)由胞浆摄入内质网腔内，而由IP3R和RyR通道释放进入胞浆，从而维持内质网中游离Ca2+稳定。由于其蛋白质折叠和转运功能，内质网存在大量Ca2+依赖分子伴侣，如钙网织蛋白和葡萄糖调节蛋白78(glucose-regulated protein 78/immunoglobulin binding protein ，GRP78/BiP)等。内质网必须严格控制Ca2+水平，避免Ca2+失衡导致细胞死亡[3]。此外，内质网质膜(plasma membrane，PM)作为其屏障可以在整个细胞自由扩散，通过一系列接触位点连接不同细胞器。越来越多的研究表明，ER-PM接触位点在维持Ca2+稳态、信号传递和脂质调节中发挥重要作用[4, 5]。遗传或环境损伤会引起细胞内钙稳态失衡、氧化应激、营养缺乏、糖基化抑制和蛋白质错误折叠，从而破环内质网功能，诱发内质网应激(endoplasmic reticulum stress，ERS)[1, 2, 3, 6]。内质网应激时蛋白质不能正确折叠积聚在内质网腔内，细胞通过PERK-eIF2α(Protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation-initiation factor 2α)、IRE1-XBP1(inositol-requiring enzyme 1a-X-box-binding protein 1)和ATF6-CREBH(activating transcription factor 6-CREBH)一系列信号网络转导途径，提高蛋白质正确折叠能力、抑制蛋白质的产生和积聚、加速非功能性和隐含毒性蛋白降解，引发内质网应激相关基因的转录和加强内质网的自我修复能力。这些反应统称为未折叠蛋白应答 (unfold protein response，UPR)，内质网应激过强或持续时间过久，这些反应不足以恢复内质网稳态，则最终引起细胞凋亡[7, 8]。
ERS的表现包括UPR、内质网相关性死亡和整合应激反应这3个交互相联的动态过程，主要为UPR。真核细胞产生ERS时，UPR激活其典型信号通路，这些信号通路根据其在内质网上发起效应器的不同分为蛋白激酶样内质网激酶(PKR like ER kinase，PERK) 、1 型内质网转膜蛋白激酶(type-1ER transmembrane protein kinase，IRE1)和活化转录因子6 (activating transcription factor 6，ATF6)3类[9]。在正常生理状态下，内质网腔区域的3个跨膜受体蛋白PERK、IRE1 和ATF6与GRP78/BiP处于结合状态，形成稳定复合物，使它们处于未激活状态。当细胞内质网中蛋白质折叠紊乱、积累大量未折叠或错误折叠蛋白质，发生内质网应激时，GRP78/BiP作为内质网稳态感受器，与3种UPR效应器PERK、IRE1 和ATF6解离，转而结合新生的未折叠蛋白，而被激活游离的3种跨膜感受蛋白则激发UPR信号级联反应 [2, 10, 11](图 1)。
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| 图 1 人类疾病中未折叠蛋白应答和内质网功能障碍信号通路间的相互作用 Fig. 1 The interplay between different signaling pathways induced in an event of unfolded protein response and subsequent endoplasmic reticulum dysfunction in human diseases |
细胞凋亡是维持机体正常功能和内环境稳定的分子调节形式，可在多种生理和病理情况下发生。细胞凋亡与很多人类疾病的发生发展密切相关，如糖尿病、肝脏疾病、神经退行性疾病等。内质网应激过强或持续时间过久则会通过UPR途径激活细胞凋亡信号通路[12, 13]。内质网应激时内质网持续释放Ca2+，细胞质Ca2+水平升高，线粒体膜电位改变[14]，从而释放细胞色素c与细胞质中Apaf1结合，Apaf 1 寡聚化后与活化的caspase-9共同组成凋亡体复合物，这些凋亡体复合物进一步激活caspase- 3和caspase- 7，导致不可逆转的细胞凋亡[15, 16]。同时内质网膜相关的caspase- 12也通过直接激活caspase- 3和caspase- 9，引起caspase级联反应，激活细胞凋亡。此外，内质网应激激活的PERK、IRE、ATF6 还可导致前凋亡基因CHOP/GADD153的转录显著上调[17, 18]，CHOP/GADD153 的过度表达也可导致细胞凋亡的发生。细胞内Ca2+水平的升高、CHOP/GADD153 mRNA和蛋白质水平的上调与caspase- 12活化有关[19, 20]。高表达的CHOP能抑制抗凋亡蛋白Bcl-2的表达，并且会引发Bax蛋白发生从细胞质向线粒体的移位，破坏Bax/Bcl-2比例[21, 22]。研究认为，Bcl-2蛋白家族定位于线粒体和内质网[23] 。当线粒体与内质网受到刺激时，这些促凋亡和抗凋亡蛋白的比例失衡，激活细胞凋亡信号。此外，CHOP/GADD153 能激活GADD34，GADD34与蛋白磷酸酶1 反应促进eIF2α去磷酸化,引起内质网蛋白超载[24, 25, 26]。UPR关键蛋白IRE1α可以直接结合肿瘤坏死因子受体相关因子(TRAF2 )，促进凋亡信号调节激酶(ASK1)及其下游激酶活化，最终通过JNK激活caspase-12，诱导细胞凋亡[27, 28]。上述报道表明内质网应激和UPR引起的细胞凋亡信号通路激活与多种人类疾病的发生发展密切相关。
2 内质网应激与氧化应激活性氧(reactive oxygen species,ROS) 、活性氮(reactive nitrogen species,RNS)是细胞受到多重刺激时细胞内不同部位大幅度产生的活性自由基[29, 30, 31]。ROS 包括超氧阴离子、羟自由基、过氧化氢，三者能促发氧化应激；RNS即一氧化氮(NO)及其代谢产物过氧亚硝酸盐(PN)。内质网正常的生理功能与氧化还原状态密切相关，越来越多的研究证明ROS和RNS在内质网应激过程中起着介导和调节作用。内质网提供一个独特的氧化环境促进蛋白质二硫键形成，进而在内质网形成ROS [32, 33, 34]。也有研究证明，未折叠蛋白在内质网的积聚引起Ca2+水平失衡，Ca2+大量释放到细胞质通过三磷酸肌醇受体(inositol trisphosphate receptor,IP3R)产生ROS[35, 36]。蛋白质在内质网腔的折叠和重折叠需要消耗大量ATP，ATP耗竭导致蛋白质错误折叠刺激线粒体氧化磷酸化增加ATP和ROS的产生。此外，内质网跨膜蛋白NADPH氧化酶复合物Nox4也可能参与超氧阴离子和过氧化氢的产生[37]。
细胞氧化应激诱导Nrf bZIP家族转录因子活化防御基因抗氧化剂[19, 38, 39]。研究表明，Nrf bZIP家族蛋白可能与内质网应激防御有关。已有研究报道Nrf1蛋白和Nrf3蛋白与内质网膜及核膜相关，表明它们参与内质网相关功能[40, 41]。PERK激活Nrf2[16]，Nrf2通过转录抗氧化酶调节细胞抗氧化应激保护机制。在内质网应激时，PERK调节Nrf2磷酸化[42, 43]，Nrf2积聚在细胞核，与抗氧化剂相应元件(ARE)结合诱导血红素氧合酶-1、谷胱甘肽-S-转移酶等抗氧化酶转录[16](图 1)。因此，协调内质网和细胞质间动态平衡对细胞应激防御具有重要作用，而内质网信号传递在这个过程中起着关键作用。
3 内质网应激与炎症反应内质网应激反应能够与细胞内炎症反应信号转导通路偶联，是非感染性致病原引发炎症反应的主要原因。因此，内质网应激及炎症反应与呼吸道、心血管、神经退行性疾病、癌症和糖尿病等众多疾病的发病机制有关[44, 45, 46, 47]。UPR通过PERK,IRE1和ATF6 3条信号通路激发炎症反应，进而激活NF-κB信号通路 [48, 49] 。NF-κB在炎症反应发生过程中发挥主导作用，能够促进大量促炎症细胞因子基因的表达。NF-κB一般存在与细胞质中，与IκB蛋白结合形成复合物，使其处于非活性形式，阻止其活化和核易位。急性或慢性应激导致IκB蛋白降解活化NF-κB。研究表明IRE1α通过降解IκB蛋白引起NF-κB活化及核易位，而PERK通过抑制IκB翻译激活NF-κB。此外，IRE1可以激活转录因子AP1，进而诱导肿瘤坏死因子(tumor necrosis factor,TNF) 、角质细胞生长因子(keratinocyte growth factor,KGF) 、粒细胞巨噬细胞集落刺激因子(granulocyte macrophage colony-stimulating factor,GMCSF) 、白细胞介素(interleukin,IL-8)和某些细胞因子受体的表达[50, 51, 52]。UPR的ATF6通路参与激活组织损伤、感染和炎症等产生的急性应急期。血清急性期蛋白(APPs)浓度升高，最终引起发热、神经和病理变化。
最近研究发现，NLRP3炎性复合物是一种先天免疫信号受体，在调节细胞对各种内源性和外源性信号的反应中发挥关键作用。同时研究表明，炎性复合物在许多自身免疫和代谢性疾病中起着关键作用。NF-κB激活IL1b前体，通过NLRP3、ASC 和 caspase-1复合物将其转化为成熟IL1b[53, 54]。此外，ROS和溶酶体损伤也会激活NLRP3炎性通路，诱导促炎症反应。研究证明，内质网应激可以通过NF-κB通路诱导IL1b前体和NLRP3炎性复合物活化[55, 56]。因此我们推测内质网应激与炎症及炎症相关疾病有关。
4 内质网应激与疾病 4.1 内质网应激与骨质疏松症骨质疏松症(osteoporosis,OP)是一种老年人常见的以骨骼疼痛、骨强度降低、骨脆性增加及骨组织微结构退变为特征的全身性代谢性疾病。骨质疏松症以低骨矿密度(bone mineral density,BMD)为标志，而低BMD与内质网应激有关。机体出生后胰腺和骨骼肌系统生长发育需要通过PERK-eIf2α信号通路[57, 58]。ATF4 是 PERK 通路下游靶分子，ATF4 可协同 cbfa1 刺激成骨细胞内骨钙蛋白(osteocalcin,OCN)的表达，表明 ATF4 在成骨细胞分化、成熟和骨骼发育过程中有重要作用。成骨细胞和破骨细胞间的平衡对骨骼正常生长发育非常重要[59, 60]。研究报道，磷酸酶抑制剂Salubrinal可以通过抑制eIF2α去磷酸化增加成骨细胞分化。因此推测可以通过eIF2α和ATF4调节内质网应激进而对抗骨质疏松症[61]。糖尿病患者髋部和上肢易患骨折[62]，因为胰岛素缺乏和高血糖引起低BMD，损害骨骼形成[63]。此外，据报道糖尿病本身能诱导内质网应激特征性凋亡通路CHOP在成骨细胞中表达，导致成骨细胞凋亡[64]。因此，成骨细胞与破骨细胞比例失衡引起骨骼疾病最终发展为糖尿病骨质疏松症[64]。在病理条件下，IRE1α-XBP1通路在成骨细胞成熟、骨形成和骨吸收过程中发挥重要作用[65]。此外，研究报道骨质疏松症患者成骨细胞的内质网特异性分子伴侣，如GRP78/BIP和蛋白质二硫键异构酶(protein-disulfide isomerase，PDI)减少[66]。这些发现表明，内质网应激与骨质疏松症、骨骼发育密切相关，内质网应激可以作为治疗骨骼疾病的靶点。
4.2 内质网应激与癌症众多研究已经确认肿瘤和癌症的发生发展密切相关，许多种类的癌细胞都依赖于内质网分子伴侣的高蛋白质合成和折叠能力来保证癌细胞的生长增殖和扩散。肿瘤细胞生长时缺氧、氧化还原失衡、pH波动和营养供不应求的微环境特点诱导UPR发生[67]。此外，研究发现肿瘤细胞的UPR信号传递增加[68]。一些内质网应激反应中的关键分子已经被证明对肿瘤的发生是必需的。例如，GRP78/BiP 蛋白在多种癌症，如前列腺癌、乳腺癌、肺癌、黑色素瘤和结肠癌细胞等中都是高表达的[69, 70, 71, 72, 73, 74, 75, 76]。研究证明GRP78/BiP 蛋白对肿瘤的发生是必需的[77]，GRP78/BiP可以通过增加内质网的蛋白质折叠能力从而加强肿瘤细胞的生长增殖和抑制肿瘤细胞的凋亡。此外，研究表明GRP78 可以溶解抵抗CTL 和TNFα，协助癌细胞逃避自身免疫系统的监视，对癌细胞的扩散和转移有重要作用。UPR的PERK通路也在肿瘤细胞的增殖和存活过程中起着重要作用。在极端缺氧环境下，PERK的激酶结构域发生突变或eIF2α形成磷酸化抗性导致PERK失活，损坏细胞存活[78]。此外，PERK可以通过激活Nrf2限制DNA的氧化应激损伤，进一步促进肿瘤细胞生长增殖[79]。因此，UPR有望成为癌症的新的有效治疗靶点[80]。
在不同应激条件下激活的肿瘤抑制基因TP53在促进细胞周期停滞、衰老和凋亡等生物学机制中起着关键作用[81, 82, 83, 84] 。TP53是否与内质网应激有关还无法定论。有研究表明，内质网应激能稳定p53活性，诱导p53介导的细胞凋亡。也有研究报道，内质网应激通过Gsk3β诱导p53表达下调[85, 86]。此外在临床环境下，肿瘤的发生发展及其治疗功效可能与内质网应激抑制p53的能力有关。因此，抑制内质网应激可能是抑制癌症发展、增加癌症疗效的有效策略。
4.3 内质网应激与退行性神经疾病神经退行性疾病的发病机制复杂多样，包括氧化应激、内外环境因素、遗传倾向、谷氨酸诱导的兴奋性中毒、神经营养及可塑性改变、线粒体功能障碍和错误折叠蛋白的积聚等。本综述该部分主要讨论内质网应激的UPR激活与神经退行性疾病的关系。错误折叠蛋白积累是包括阿尔茨海默病、帕金森病和亨廷顿氏舞蹈病等神经退行性疾病的一个显著特征[87, 88]。正如前文所述，错误折叠蛋白积累会引起内质网应激，激活UPR。内质网应激诱导细胞死亡和UPR可能与神经退行性疾病发病机制有关，我们将讨论UPR与阿尔茨海默病和帕金森病这两个主要神经退行性疾病的关系。
4.3.1 内质网应激与阿尔茨海默病阿尔兹海默病(Alzheimer’ s disease ,AD)是最常见的神经退行性疾病，其主要病理特征是β淀粉样蛋白沉积形成神经炎性斑块和tau 蛋白过度磷酸化形成神经元纤维缠结(neurofibrillary tangle，NFT) [89]。β淀粉样蛋白是由β-淀粉样前体蛋白( β-amyloid precursor protein，APP) 通过β-分泌酶和γ-分泌酶水解形成的。研究显示，内质网应激效应器IPE1和PERK与早衰蛋白密切相关，而早衰蛋白是主要存在于内质网膜的跨膜蛋白，并且在内质网和高尔基体内大量表达[90]。一些研究发现，s早衰蛋白突变不仅可导致细胞内Ca2+失衡、氧化应激等凋亡刺激的易感性增加，并且对内质网应激的易感性也增加。早衰蛋白突变抑制PERK-eIf2α通路磷酸化，导致蛋白质在内质网积聚[91]。还有研究发现，AD大脑海马神经元的PERK和eIf2α水平升高[92, 93]。此外，突变早衰蛋白1通过抑制IRE1信号通路抑制内质网转录分子伴侣，如GRP78的表达[91]。XBP1也和AD有关，可以控制多种细胞转录调控相关信号[94]。调节IRE1可以减少或延缓XBP1的拼接，从而切换信号到促死亡反应[95]。
Aβ的产生是AD特征性标志，Aβ聚集导致老年斑形成、造成突触损失、神经功能失调和神经元死亡，而Aβ的产生与内质网有关[96, 97]。文献报道Aβ可以诱导内质网储存的Ca2+向胞浆释放[98]，同时质膜和内质网膜Ca2+的大量涌出也通过改变Aβ的代谢促进Aβ产生增加[99]。另外，许多内质网相关分子伴侣，如GPR78 等都是Ca2+ 结合蛋白，内质网内的Ca2+耗竭可以影响这些蛋白质的功能进而影响蛋白质的合成与折叠过程，加重内质网应激从而导致细胞损害。因此，细胞内Ca2+系统紊乱可能是Aβ引起的内质网应激的重要环节之一。毫无疑问，Ca2+功能紊乱和AD存在错综复杂的关系[100]。因此，Ca2+的动态平衡是内质网分子伴侣和蛋白质折叠功能正常运行的保障。AD的另一个特征性标志Tau蛋白是存在于神经元细胞的微管相关蛋白，维持微管装配和稳定。内质网应激通常与Tau蛋白的早期病理阶段有关[101, 102]。正常情况tau 蛋白的磷酸化和去磷酸化处于动态平衡，当机体由于某些原因发生异常时导致tau 过度磷酸化形成有毒双螺旋纤维丝[103]。已有研究表明，AD患者海马神经元未折叠蛋白应答的激活与磷酸化的tau(p-tau)和GSK-3β的存在密切相关[93]。这些发现表明AD神经元未折叠蛋白应答激活发生在神经元纤维变性的早期阶段。此外，持续的UPR可能参与tau 磷酸化和AD的神经退行性病变[104]。
4.3.2 内质网应激与帕金森病帕金森病(Parkinson’s disease ，PD)的主要病理特征是中脑黑质多巴胺能神经元变性坏死和路易小体形成[105]。越来越多的人类PD遗传或毒理学模型研究表明内质网应激是PD发病的共同特征，并且能够促进神经变性[106, 107]。研究表明内质网应激效应蛋白ATF6α和剪接XBP1过表达限制神经毒性物质诱导多巴胺能神经元死亡[108, 109]。这些研究表明，内质网应激在PD模型死亡和多巴胺能神经元功能紊乱过程起着重要作用。
研究证明，α突触核蛋白和parkin相关内皮素受体样受体Pael-R等错误折叠蛋白积累是触发内质网UPR的关键因子。α突触核蛋白是一种在突触小泡和神经组织表达的常染色体显性遗传PD基因。正常情况下α突触核蛋白是可溶性存在的，翻译后修饰，如α突触核蛋白磷酸化和亚硝基化可能导致异常折叠变成不可溶性蛋白并沉积于PD患者黒质的路易小体[110]。Smith等[111]研究报道，α突触核蛋白突变型A53T异常表达激活UPR，CHOP和GRP78表达升高，eIf2α磷酸化水平上调。此外，Smith等称可以通过抑制eIf2α磷酸化抑制UPR从而保护α突触核蛋白A53T突变型过表达。这些研究表明，UPR介导细胞凋亡的动态平衡[111]。另外，常染色体显性遗传性PD 基因LRRK2(leucine-rich repeat kinase 2)突变会导致蛋白质降解通路和自噬溶酶体通路损伤，氧化蛋白、α突触核蛋白和泛素蛋白积聚[112]。LRRK2定位于路易小体的核心部位[113]，可以上调GRP78(内质网应激时关键存活分子)的表达[114]。除了α突触核蛋白和LRRK2，散发性PD路易小体核心也检测到Pael-R积聚[115]。常染色体隐形PD基因Parkin编码一种E3泛素连接酶，错误折叠 Pael-R蛋白代谢依赖于Parkin蛋白介导的泛素化和蛋白酶体降解[116]。Parkin基因突变导致E3连接酶突变失活引起错误折叠 Pael-R在细胞内异常聚积,引起内质网应激，最终诱发细胞凋亡[117]。因此，错误折叠 Pael-R积累引起内质网应激可能是常染色体隐形遗传PD的另一个发病机制[118, 119, 120]。
上述关于AD和PD的论述充分表明内质网应激与这些疾病的发生发展密切相关。文献报道内质网应激同样参与其他退行性神经疾病，如肌萎缩性脊髓侧索硬化、亨廷顿氏舞蹈病和朊病毒疾病等[104, 120]。
5 小结及展望内质网在蛋白质合成和折叠过程起着至关重要的作用，未折叠或错误折叠蛋白在内质网蓄积引发内质网应激,导致细胞内稳态失衡，其主要后果是细胞凋亡,从而对机体组织和器官造成损伤。近年来，文献报道内质网应激与细胞凋亡和多种疾病的发生发展都密切相关，对内质网应激作用机制的研究可以加深我们对这些疾病发病机制的了解，对开发和探索内质网应激相关疾病治疗靶点也有重要意义。
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