2019, Vol. 54
表1(Table 1)
赖氨酸乙酰化的研究进展及应用
杨雨薇,
尚爽,
胡卓伟,
花芳
引用本文
YANG Yu-wei, SHANG Shuang, HU Zhuo-wei, HUA Fang. Advances and applications of lysine acetylation[J]. Acta Pharmaceutica Sinica, 2019, 54(5): 778-787. 
杨雨薇, 尚爽, 胡卓伟, 花芳. 赖氨酸乙酰化的研究进展及应用[J]. 药学学报, 2019, 54(5): 778-787.
赖氨酸乙酰化的研究进展及应用
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 新药作用机制研究与药效评价北京市重点实验室(BZ0150), 北京 100050
摘要:
蛋白质乙酰化是指在乙酰基转移酶的作用下，蛋白质的赖氨酸残基添加乙酰基的过程。它是连接乙酰辅酶A代谢与细胞信号转导的重要蛋白质翻译后修饰类型。近年来，质谱鉴定的发展提高了研究者对赖氨酸乙酰化的认识，赖氨酸乙酰化参与基因转录、蛋白降解、细胞代谢、应激反应等多个细胞过程，通过调节蛋白质相互作用、活性、稳定性和定位影响其生物学功能，在代谢相关疾病、肿瘤、心血管疾病等多种疾病中发挥重要调控作用。目前，去乙酰化酶抑制剂已经在肿瘤、代谢相关疾病及其他多种疾病中显示出巨大的治疗潜力。本文围绕乙酰化的研究历程、生物学功能及应用进行了归纳和探讨，并对未来研究进行了展望和讨论。
关键词:
乙酰化作用
代谢
蛋白质修饰
转译
Advances and applications of lysine acetylation
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150), Institute of Meteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Protein acetylation is a process of adding an acetyl group to a protein lysine residue with the help of acetyltransferase, which is a pivotal protein post-translational modification linking acetyl-CoA metabolism and cell signal transduction. Recently, the development of mass spectrometry has deepened our understanding of lysine acetylation. Lysine acetylation is involved in many processes such as gene transcription, protein degradation, cellular metabolism, and stress response, which affects biological processes by regulating protein interactions, activity, stability and localization. Protein acetylation is widely happened and plays important regulatory roles in a diversity of human diseases such as metabolic diseases, tumors and cardiovascular diseases. Besides, deacetylase inhibitors have displayed a great potential in the treatment of various diseases especially tumors and metabolic associated diseases. In this review, we summarized the advances and application of acetylation, and discussed the remaining problems in this area.
Key words:
acetylation
metabolism
protein modification
translational
蛋白质乙酰化是蛋白质翻译后修饰的主要形式之一, 是乙酰基供体(如乙酰辅酶A)通过酶学或非酶学的方式将乙酰基团共价结合到赖氨酸残基上的过程。此外, 蛋白质也可发生其他酰基化修饰, 如丙酰化、丁酰化和琥珀酰化。其中, 蛋白质乙酰化参与了机体多种病理、生理过程调节, 是近年来的研究热点。
乙酰化修饰是在细胞核或细胞质的亚细胞器内广泛存在的翻译后修饰调控机制, 参与了转录、趋化、新陈代谢、细胞信号转导、应激反应、蛋白质水解、细胞凋亡, 以及神经元的发育等多个过程。乙酰化修饰是一个动态可逆的过程, 有3类蛋白质参与了乙酰化修饰调节:赖氨酸乙酰转移酶(lysine acetyltransferase, KAT)负责将乙酰基团共价连接到蛋白的赖氨酸残基上, 被形象地称为“书写者(writer)”; 而赖氨酸去乙酰化酶(lysine deacetylase, KDAC)则介导将乙酰基团从蛋白质中的赖氨酸残基上移除, 被称为“橡皮擦(eraser)”; 赖氨酸的乙酰化修饰为乙酰化赖氨酸结合蛋白, 如溴结构域蛋白提供结合信号, 使之选择性与乙酰化蛋白相互作用, 这些蛋白被称为“读者” (reader)。目前在哺乳动物中已知的乙酰化酶约有20多个[1, 2], 主要分为3个家族: GNAT家族、CBP/p300家族和MYST家族[3]; 去乙酰化酶根据其催化机制不同分为两类: Zn2+依赖的组蛋白去乙酰化酶(histone deacetylase, HDAC)家族[4]和NAD+依赖的Sirtuin (SIRT)家族[5] (图 1A)。溴结构域(bromodomains, BRDs)蛋白通过识别和结合乙酰化赖氨酸残基, 在基因表达和表观遗传方面发挥重要调节作用[6]。
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Figure 1 Metabolites regulate acetylation and deacetylation. A: The metabolism of acetyl-coenzyme A (acetyl-CoA) mediates lysine acetylation. Acetylation is catalyzed by lysine acetyltransferase (KATs) with acetyl-CoA as a cofactor and reversed by lysine deacetylase (KDACs). Acetyl-CoA can also mediate acetylation of lysine non-enzymatically; B: NAD+ is an essential cofactor for sirtuin deacylase. Inositol 1, 4, 5, 6-tetraphosphate (Ins(1, 4, 5, 6)-P4) binds to HDAC1, HDAC2 and HDAC3, then increases the catalytic activity of these deacetylases. These enzymes are inhibited by several other metabolites, including D-β-hydroxybutyrate (βOHB), L-carnitine, and sphingosine phosphate (S1P) |
本综述首先概述了乙酰化研究的发展历程, 然后讨论了赖氨酸乙酰化修饰介导的主要细胞生物学功能, 最后探讨了乙酰化在多种疾病发生、发展过程中的作用和机制及其在治疗学中的意义。
1 赖氨酸乙酰化的研究历程1964年, 研究者发现组蛋白的赖氨酸存在可逆的乙酰化修饰[7]。此后, 人类对蛋白质乙酰化的研究越来越广泛, 且研究主要集中于组蛋白。与此同时, 蛋白质磷酸化参与细胞信号转导的关键调节作用开始受到研究者重视, 由于检测技术的突破, 蛋白质磷酸化修饰研究领域迅速发展。相比之下, 由于乙酰化位点鉴定受到技术层面的限制, 使得这一领域的研究相对滞后。从发现组蛋白乙酰化到开始研究非组蛋白乙酰化历经20余年[8]。20世纪90年代, 肿瘤抑癌基因p53和人类免疫缺陷病毒HIV转录调控蛋白Tat相继被发现受到乙酰化修饰的调节[9]。
近年来, 基于高分辨率质谱的蛋白质组学在技术层面取得突破性进展, 能够实现从单个实验中鉴定出数千个乙酰化位点, 并对乙酰化修饰水平进行相对定量, 开创了乙酰组学研究时代[10, 11]。
2 赖氨酸乙酰化的调节及生物学功能乙酰化修饰在细胞内广泛存在, 其修饰程度受机体代谢状态的精细调控。蛋白乙酰化修饰对蛋白质功能具有重要调节作用, 参与基因转录、蛋白降解、细胞代谢、应激反应等多个细胞过程。
2.1 代谢产物参与调节赖氨酸乙酰化和去乙酰化细胞信号传导可以对营养素和生长因子产生应答, 进而调节机体代谢过程。近来的研究证据显示, 细胞代谢物特别是代谢中间体直接参与调节赖氨酸乙酰化修饰[12-14]。
乙酰辅酶A是乙酰转移酶催化赖氨酸残基乙酰化修饰的辅因子。它是碳分解代谢途径和能量代谢中的关键中间体, 这些代谢过程包括糖酵解和丙酮酸氧化, 以及脂肪酸β-氧化。不同组织中, 乙酰辅酶A的含量不尽相同[12, 15]。乙酰辅酶A可以调节细胞中蛋白乙酰化水平。乙醇可以代谢成乙酰辅酶A, 在乙醇诱导肝损伤的大鼠和小鼠模型中, 可观察到蛋白乙酰化水平受到乙醇影响[16]。在酵母中的研究发现, 乙酰辅酶A代谢紊乱影响芽生酵母中的乙酰化修饰水平[17]。尽管乙酰化与乙酰辅酶A的产生相关, 但乙酰辅酶A水平是否对所有KATs的活性具有限速作用尚不清楚, 因为大多数KATs对乙酰辅酶A具有低于生理乙酰辅酶A浓度的结合亲和力[18]。一些KATs对辅酶A具有与对乙酰辅酶A相似的亲和力, 结合辅酶A可以抑制KATs活性, 因此乙酰辅酶A与辅酶A的比率可能是调节KAT活性更重要的指标。此外, 乙酰辅酶A可能对赖氨酸残基进行非酶促乙酰化修饰, 并且这种乙酰化严格依赖于乙酰辅酶A的浓度。此外, 通过生理或遗传操作手段影响乙酰辅酶A代谢也可对乙酰化水平产生影响[17]。
近年来, 人们发现一些非乙酰化代谢物是去乙酰化酶的重要调节剂(图 1B)。如二核苷酸NAD+是参与细胞电子传递链的关键代谢物, 它在去乙酰化酶发挥介导蛋白去乙酰化过程中扮演必需辅助因子的角色[19]。去乙酰化酶催化的去乙酰化将NAD+转化为烟酰胺, 它可作为去乙酰化酶活性的竞争性抑制剂[20]。NAD+/NADH比率反映了细胞氧化还原状态, 可影响去乙酰化酶活性, 从而影响蛋白乙酰化水平。禁食或卡路里限制期间出现的代谢产物D-β-羟基丁酸酯(Dβhydroxybutyrate, βOHB)水平升高, 与组蛋白乙酰化修饰增高有关[21]。βOHB能与HDAC1、HDAC2和HDAC3结合, 并抑制它们的活性, 导致组蛋白乙酰化升高。代谢物左旋肉碱(L-carnitine)是活细胞中产生代谢能量的必需物质, 可抑制HDAC1和HDAC2, 从而增加组蛋白乙酰化[22]。脂质介质鞘氨醇-1-磷酸(sphingosine-1-phosphate, S1P)也能与HDAC1和HDAC2结合并抑制其去乙酰酶活性[23], 而丙酮酸能抑制HDAC1和HDAC3的活性。有趣的是, HDAC1、HDAC2和HDAC3也与肌醇-1, 4, 5, 6-四磷酸[Ins (1, 4, 5, 6) P4]结合, 增加去乙酰酶的催化活性[24]。细胞代谢物影响蛋白的乙酰化和去乙酰化修饰, 这意味着蛋白质乙酰化可以反映细胞代谢状态。细胞代谢状态与机体可利用的营养物水平相关, 因此乙酰化和其他营养敏感的翻译后修饰可以作为将代谢与基因表达调控程序联系起来的评价指标。
2.2 赖氨酸乙酰化参与转录活性调节机体通过调控DNA结合蛋白、转录因子或者与转录相关蛋白的乙酰化来控制基因表达。组蛋白乙酰化与转录活性密切相关, 高乙酰化组蛋白特异地聚集于活性染色质功能区。SIRT2催化H4K16去乙酰化, 维持浓缩的异染色质状态, 关闭基因转录; 而组蛋白H4K16乙酰转移酶Sas2则抵消了这种作用[25]。用TSA (trichostatin A)抑制去乙酰化酶后, 组蛋白H4乙酰化程度提高, 可引起人类脐静脉内皮细胞中组织纤溶酶原激活因子产量增加[26]。
自从发现第一个非组蛋白p53的赖氨酸乙酰化修饰以来, 越来越多的非组蛋白赖氨酸乙酰化修饰相继被发现, 这其中有很多是转录因子。如p300/CBP介导p53的C端结构域发生多个赖氨酸位点的乙酰化修饰, 激活p53的DNA结合区域活化; 同时, HDAC1和SIRT1等去乙酰化酶也可调控p53的转录活性。SIRT1可介导p53蛋白K382位点的去乙酰化, 从而抑制p53对下游靶基因, 如p21以及BAX等的转录激活作用[27]。本课题组最近的研究发现, 应激蛋白TRIB3可通过增强乙酰化转移酶KAT5与转录因子SMAD3的相互作用而增强SMAD3第333位赖氨酸乙酰化, 维持SMAD3转录活性并诱导TRIB3表达[28]。可逆的赖氨酸乙酰化修饰在转录因子中广泛存在, 乙酰化酶和去乙酰化酶通过调节转录因子或辅助因子的乙酰化修饰, 调控细胞的转录过程, 进而影响细胞的生命活动。
2.3 赖氨酸乙酰化参与蛋白稳定性调控蛋白质乙酰化修饰还参与了蛋白稳定性调控[29]。核糖核酸酶RNase R存在于细菌中, 对细菌的生存至关重要。RNase R的表达受多种逆境诱导, 乙酰化修饰能促进tmRNA和SmpB复合物的结合, 改变RNase R的结构, 从而导致其被蛋白酶降解。在逆境条件下, RNase R乙酰化水平降低, 稳定性得以保持[30, 31]。帕金森疾病和阿尔茨海默症以Tau蛋白过度磷酸化为特征, 如降低Tau水平可改善帕金森疾病和阿尔茨海默症[32]。研究发现, 乙酰转移酶p300和去乙酰化酶SIRT1可以调节Tau的乙酰化。Tau的乙酰化水平增加可抑制磷酸化Tau的降解。抑制乙酰化酶p300, 可以促进Tau去乙酰化, 降低Tau的磷酸化, 从而促进Tau的降解。调节Tau乙酰化可能是减少Tau介导的神经病变的新治疗策略[33]。脂肪酸合成酶(fatty acid synthase, FASN)是新生脂肪形成的终末酶, 其抑制剂在治疗癌症、肥胖症和其他疾病中的作用已进入临床试验阶段, 是治疗代谢相关多种疾病的重要潜在靶点。研究表明, 去乙酰化酶HDAC3逆转乙酰化酶KAT8对FASN的乙酰化修饰, 减弱FASN与E3泛素连接酶Trim21的相互作用, 从而维持其在细胞中的稳定性。HDAC3可通过增加FASN的蛋白水平促进肿瘤细胞脂肪生成并促进肿瘤细胞生长[34], 提示HDAC3介导的FASN去乙酰化是肿瘤治疗的潜在靶点。
2.4 赖氨酸乙酰化与其他蛋白质翻译后修饰相互调控翻译后修饰是调控蛋白质功能的重要机制, 目前, 多种蛋白翻译后修饰被深入探讨, 包括泛素化、磷酸化、琥珀酰化等[35]。赖氨酸乙酰化可以和其他翻译后修饰相互影响, 相互协调, 从而调控整个细胞信号通路。
泛素化是广泛存在的蛋白质翻译后修饰, 参与了蛋白质稳定性及多种功能调控。乙酰化与泛素化密切相关, 相互之间存在交互调控。如中心体蛋白PLK2乙酰化可以抑制其泛素化; 同时, 去乙酰化酶SIRT1介导的去乙酰化可促进PLK2泛素化降解[36]。泛素分子本身的乙酰化修饰则会抑制多泛素链的延长[37]。反之, 泛素化修饰也参与了乙酰化修饰调控。组蛋白去乙酰化酶SIRT1在DNA损伤应答过程中具有重要作用。MDM2可介导SIRT1泛素化修饰, 这种修饰在不同的DNA损伤情况下, 对SIRT1的稳定性和酶活性起到不同的调节作用, 从而对乙酰化修饰进行调控[38]。蛋白质磷酸化是一种可逆的翻译后修饰, 对蛋白质合成、细胞增殖、细胞凋亡和信号转导等至关重要。研究发现, 蛋白质的乙酰化与磷酸化相互调节, 在心脏中, 组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACIs)在应激条件下抑制了磷酸酶基因表达, 并且HDACIs抑制剂对蛋白质乙酰化的改变, 导致双特异性磷酸酶5和细胞外信号调节激酶1/2的去磷酸化, 减轻应激性心脏肥大。因此, HDACIs可以调节乙酰化-磷酸化的串扰从而调节心脏功能[39]。
2.5 赖氨酸乙酰化参与氧化应激调节活性氧(reactive oxygen species, ROS)是一类性质活泼的含氧分子。在细胞信号传导中起重要的调节作用。在线粒体中, ROS为氧化能量代谢的副产物。ROS过度产生与癌症、糖尿病、动脉粥样硬化、神经退行性疾病和类风湿性关节炎等疾病的发病有关。过量的ROS造成胞内蛋白质和DNA等生物大分子氧化损伤, 导致细胞处于氧化压力下, 产生氧化应激反应[40, 41]。
赖氨酸乙酰化可以增强大肠杆菌抵抗外界环境刺激的能力。如在大肠杆菌中, 通过提高乙酰转移酶YfiQ的浓度增加蛋白乙酰化水平, 可提高大肠杆菌抗热和抗氧化能力[42]; 而去乙酰化酶CobB过量则产生相反的作用[43]。在哺乳动物中, 超氧化物歧化酶2 (superoxide dismutase 2, SOD2)位于线粒体中, 发挥消除氧化压力的作用。SOD2受乙酰化修饰调控, 去乙酰化酶SIRT3可激活SOD2, 提高细胞自我保护能力, 减少氧化损伤[44, 45]。异柠檬酸脱氢酶2 (isocitrate dehydrogenase 2, IDH2)也位于线粒体中, 可帮助细胞提高抗氧化能力。去乙酰化酶SIRT3可激活IDH2, 提高其催化能力以及NADPH的水平, 从而降低细胞氧化损伤[46]。在胞浆中, 葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase, G6PD)是磷酸戊糖途径的关键酶, 通过催化产生细胞内重要的还原剂NADPH。氧化刺激可激活去乙酰化酶SIRT2, 降低G6PD乙酰化水平, 提高其催化活力。这种调控机制可保护机体内红细胞免受氧化物质威胁[47]。
2.6 赖氨酸乙酰化参与调控相变细胞内含有多种无膜细胞器, 如应力颗粒(stress granules, SGs), 可以控制不同的细胞生物学进程。含有内在无序区(intrinsically disordered regions, IDRs)的蛋白质的液-液相分离(liquid-liquid phase separation, LLPS)是一种无膜细胞器形成的机制, 严格控制IDR行为可确保LLPS仅在必要时进行。研究显示, IDR乙酰化和去乙酰化可调节LLPS和SGs的产生。RNA解旋酶DDX3X是SGs的重要组成部分, DDX3X的乙酰化破坏了液滴的形成, 抑制了IDR的LLPS。去乙酰化酶HDAC6对DDX3X-IDR的去乙酰化可增强LLPS, 有利于SG成熟。这项研究阐明了IDR的乙酰化和去乙酰化调节LLPS的新机制, 以及对体内无膜细胞器形成的作用[48]。无序微管相关蛋白Tau的神经病理学聚集体是阿尔茨海默病的标志, 蛋白Tau能够进行LLPS从而启动聚集过程。研究发现, 乙酰化转移酶P300对Tau的乙酰化, 通过抑制其LLPS过程而干扰了Tau蛋白聚集及相应微管的组装。该乙酰化过程虽然抑制了Tau蛋白聚集所产生的神经毒性作用, 但却造成因Tau蛋白失能而导致的病理反应[49]。
3 赖氨酸乙酰化在疾病发生、发展中的作用蛋白质乙酰化和去乙酰化的平衡在基因表达调控和信号转导中具有重要调节作用, 影响一系列关键的细胞过程。乙酰化修饰障碍与多种疾病发生、发展密切相关, 如代谢性疾病、肿瘤、心血管疾病、神经退行性疾病及免疫疾病等。
3.1 乙酰化参与葡萄糖代谢调控与糖尿病发生、发展乙酰化可以通过调节代谢酶活性或相关基因的表达调控血糖, 参与糖尿病发生、发展的调控。在糖尿病中, 持续性高血糖本身可以提高乙酰辅酶A的水平, 但持续的高血糖也可以增强脂肪酸的氧化, 从而产生大量的乙酰辅酶A。正是这种过量的乙酰辅酶A通过乙酰化机制攻击蛋白质, 从而导致蛋白质功能受损(图 2)。肝脏中的糖酵解和糖异生等代谢环节中, 乙酰化修饰也广泛存在。在糖尿病大鼠模型中的研究证实, 蛋白乙酰化程度高的器官易患糖尿病并发症[50]。
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Figure 2 Excess acetyl-CoA produced in diabetes increases acetylation of proteins. Excessive acetyl-CoA produced by hyperglycemia in diabetic patients increases non-enzymatic acetylation of proteins via lysine residues |
高糖诱导的蛋白乙酰化修饰参与了糖尿病的发生、发展。含有66 kDa Src同源性2结构域的蛋白质(p66Shc)是ROS的主要调节因子, 在许多组织中表达, 其通过促进氧化应激导致器官功能障碍。在脉管系统中, p66Shc诱导的ROS引起内皮功能障碍。p66Shc是赖氨酸去乙酰化酶SIRT1的直接靶标, 并且SIRT1调节的p66Shc乙酰化决定了其诱导ROS的能力。p66Shc在高葡萄糖条件下被乙酰化, 促进其丝氨酸的磷酸化并转运至线粒体, 从而促进氢过氧化物产生。SIRT1促进第81位赖氨酸去乙酰化, 全身敲入第81位赖氨酸突变p66Shc的转基因小鼠没有糖尿病氧化应激和血管内皮功能障碍。这些发现为p66Shc赖氨酸乙酰化在糖尿病中的重要作用提供了有力的实验证据[51]。目前, 开发小分子抑制剂或激活剂, 以降低赖氨酸乙酰化, 为控制糖尿病的发生、发展提供了新的潜在策略。
3.2 乙酰化影响肿瘤发生、发展赖氨酸乙酰化在肿瘤发生、发展中扮演重要的角色。研究表明, 乳腺癌、肝癌、鼻咽癌等多种肿瘤组织中均有乙酰化修饰异常, 乙酰化导致了肿瘤细胞内增殖、分化、凋亡相关基因表达紊乱。
激素代谢失调与乳腺癌密切相关, 4型17β-羟基类固醇脱氢酶(17β-hydroxysteroid dehydrogenase type 4, HSD17B4)催化雌二醇(estradiol, E2)向雌酮(estrone, E1)转化, 促进乳腺癌发生发展。E1上调HSD17B4赖氨酸669 (K669)乙酰化, 促进HSD17B4降解, K669单突变阻碍HSD17B4降解, 促进乳腺癌细胞迁移和转移。cAMP应答元件结合蛋白(cAMP response element binding, CREB)结合蛋白也被称为CREBBP或CBP, 具有乙酰化酶活性, 它和去乙酰化酶SIRT3共同调控HSD17B4的K669乙酰化水平。更重要的是, K669乙酰化与人乳腺癌组织中的HSD17B4呈负相关, 揭示了乙酰化在乳腺癌恶性进展中的关键作用[52]。肝癌(hepatocellular carcinoma, HCC)是世界上发病率较高的癌症之一。在正常氧含量状态下, 肿瘤细胞优先使用糖酵解而不是氧化磷酸化, 从而产生过量的乳酸和中间代谢产物, 这种现象称为瓦伯格效应(Warburg effect)。瓦伯格效应对癌细胞生长非常重要。果糖-1, 6-二磷酸酶(fructose-1, 6-bisphosphatase, FBP1)是糖异生中的限速酶, 在多种类型的癌症中出现表达丢失。在HCC患者肿瘤组织中FBP1表达下调, 且FBP1的表达降低与HCC预后不良相关。FBP1的低表达与HCC患者组织中高水平的HDAC1和HDAC2蛋白相关。使用HDAC抑制剂或敲低HCC细胞HDAC1或HDAC2, 可恢复FBP1表达并抑制HCC细胞生长。HDAC介导的FBP1表达抑制与FBP1增强子中组蛋白H3赖氨酸27位乙酰化(H3K27Ac)的减少相关。恢复的FBP1表达导致葡萄糖减少和乳酸分泌, 抑制了体外HCC细胞生长和小鼠肿瘤生长。因此, HDAC对FBP1的抑制对HCC的预后和治疗具有重要意义[53]。在鼻咽癌(nasopharyngeal carcinoma, NPC)中, p300表达上调, 是鼻咽癌的独立预后因素。在鼻咽癌细胞系中敲除p300后, 上皮表型标志物E-钙黏附素和α-连环素的上调; 间质表型标志物N-钙黏附素和波形蛋白的下调, 肿瘤细胞的迁移和侵袭能力明显受到抑制。p300通过促TGF-β信号通路中Smad2和Smad3的乙酰化, 促进上皮-间充质转变(epithelial-mesenchymal transition, EMT)[54]。上述研究提示, 乙酰化修饰在肿瘤发生、发展过程中具有重要调节作用, 靶向蛋白乙酰化修饰是肿瘤治疗的新思路。
3.3 乙酰化参与心血管生理和病理过程调节心脏持续的收缩决定了其对能量和ATP的高需求。心脏可以利用多种物质作为产生能量的底物, 其中脂肪酸氧化产生的ATP占了所需总量的50%~70%。心脏增加对脂肪酸的利用是肥胖和糖尿病的典型特征, 由此伴随的循环游离脂肪酸、甘油三酯增高, 以及脂肪酸氧化酶含量增加和活性增强, 促进了心肌细胞脂质堆积和功能障碍。长期高脂肪饮食喂养的小鼠, 其心脏线粒体脂肪酸氧化酶和丙酮酸氧化酶的乙酰化水平显著增加, 这种变化与线粒体乙酰转移酶相关蛋白(GCN5-like protein 1, GCN5L1)丰度增加有关。在H9C2细胞中敲低GCN5L1可降低线粒体脂肪酸氧化酶的乙酰化水平, 继而降低细胞内脂肪酸氧化[55]。
血管内皮功能紊乱是引发心血管疾病的主要原因, 而内皮细胞功能障碍的特征之一是合成一氧化氮(nitric oxide, NO)不足。内皮细胞中负责合成NO的酶主要是内皮一氧化氮合酶(endothelial nitric oxide synthase, eNOS)。SIRT1和eNOS相互作用可降低后者乙酰化水平, 激活eNOS活性, 催化内皮细胞产生一氧化氮, 促进血管舒张[56]。血管紧张素Ⅱ在包括衰老、心血管疾病和肾脏疾病在内的多种疾病的病理生理学中具有重要意义, 是一种多功能激素。转录激活因子PGC-1α是能量代谢和ROS清除酶的关键调节因子。血管紧张素Ⅱ可以增强乙酰化酶GCN5诱导的PGC-1α乙酰化, 从而抑制过氧化氢酶转录[57]。这些研究提示, 蛋白乙酰化修饰在心血管生理和病理过程中发挥了重要调节作用。
4 赖氨酸乙酰化修饰的应用转化乙酰化的失调涉及许多人类疾病, 如乙酰转移酶CBP和p300的突变经常在肿瘤中检测到[58, 59]。靶向参与乙酰化调节的蛋白质, 如HDACIs[60]和含溴结构域蛋白质[61]的小分子抑制剂已经显示出治疗多种疾病的潜力。靶向参与乙酰化信号传导的蛋白质为医学干预开辟了新途径。
以抗肿瘤药物为例, HDACIs作为一类新型抗肿瘤药物, 能抑制肿瘤发生、发展和转移。Romidepsin (FK-228)是用于治疗皮肤T细胞淋巴瘤(cutaneous T-cell lymphoma, CTCL)和外周T细胞淋巴瘤(peripheral T-cell lymphomas, PTCL)的组蛋白去乙酰化酶抑制剂。FK-228在低浓度下对HDAC1和HDAC2具有抑制作用, 抗肿瘤功效已在多种癌症模型中得到证实[60]。目前, 多种HDACIs已进入临床试验, HDACIs在临床试验中不仅展现了良好的抗肿瘤效果, 而且具有毒副作用小的特点(表 1)[62-97]。
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Table 1 Specific histone deacetylase (HDAC) inhibitors in cancer therapy. CTCL: Cutaneous T-cell lymphoma; PTCL: Peripheral T-cell lymphomas |
BRDs是一种能识别乙酰化赖氨酸残基的蛋白结构域。含有溴结构域的蛋白质作为肿瘤抑制因子, 参与抑制肿瘤形成和生长。BRD7是哺乳动物SWI/SNF (switch/sucrose non-fermenting)复合物的组分, 其在结肠癌细胞系、癌组织及卵巢癌组织中的表达较正常组织降低。研究发现, SWI/SNF复合物在特定组织中, 通过调控其乙酰化而抑制肿瘤的生长[6]。在Trim家族中, 含溴结构域蛋白质Trim24可以在不同肿瘤类型中突变或过表达。相比之下, Trim24还与其他Trim家族成员(如Trim28和Trim33)形成复合物, 复合物与视黄酸受体的配体相互作用, 导致其乙酰化水平降低, 转录活性的抑制, 从而产生抑瘤效果[98]。这些发现显示了含溴结构域蛋白质在肿瘤治疗领域的潜力。
除肿瘤外, 赖氨酸乙酰化在其他疾病的治疗中也颇具潜力。研究发现, 乙酰化功能可抑制人巨细胞病毒(human cytomegalovirus, HCMV)产生, 在病毒感染条件下, 乙酰化增多, K134R突变导致细胞核中病毒衣壳无法穿过细胞核膜。蛋白质乙酰化的动态变化是细胞防御和病毒入侵的关键点[99]。超罕见发育障碍的病因谱仍有待完全确定, MSL3编码了染色质相关的雄性特异性致死(male-specific lethal, MSL)复合物的成员, 该复合物促进苍蝇和哺乳动物体内的大量组蛋白H4赖氨酸16乙酰化(histone H4 lysine 16 acetylation, H4K16AC), 研究发现, HDACIs可重新平衡乙酰化水平, 减轻患者症状[100]。
5 未来展望赖氨酸乙酰化和去乙酰化在体内处于动态平衡, 维持细胞稳态。除了乙酰化以外, 各种类型的赖氨酸酰化都可能在细胞信号传导中起重要作用, 而这些酰化修饰还有很多科学问题有待解决。如是否所有酰基化都被酶调节, 它们是否以位点选择性方式被催化？酰化是否发生在不同的亚细胞区域？不同的乙酰化会介导不同的功能, 它们之间是否存在交互调节？随着蛋白质检测技术的迅速发展, 如高分辨率质谱技术和蛋白质芯片的广泛应用, 将帮助研究者加深对酰基化调节机制的理解, 而对这一领域的研究将极大丰富研究者对生命的认识, 为疾病治疗提供更多机会。
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