武汉云克隆科技股份有限公司

STAT家族蛋白：细胞命运的“指挥官”，疾病发展的关键推手

1. STAT家族简介

信号传导子和转录激活子（STAT）家族是一类关键的细胞内蛋白，充当细胞质信号传导分子和核转录因子的双重角色。当细胞因子、生长因子或激素等信号分子与细胞表面受体结合后，STATs就会被激活。激活的STATs形成二聚体，转运到细胞核内，直接结合特定DNA序列，调控靶基因的表达，从而介导细胞增殖、分化、存活、免疫应答和炎症等多种重要的细胞过程。

1.1 STAT家族结构

STATs是JAKs下游的信号分子。哺乳动物中有7个STAT家族成员（STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B和STAT6），它们在各种生理和病理过程中扮演着独特且有时重叠的角色。STATs由750-900个氨基酸组成。从N端到C端，由N端结构域、卷曲螺旋结构域、DNA结合结构域、连接结构域、SH2结构域和转录激活结构域组成。六个结构域调节STATs的不同功能：（1）N端结构域促进STATs二聚体的形成，从而使其能够与转录因子结合；（2）卷曲螺旋结构域与调节蛋白有关，并参与STATs核导入和导出过程的控制；（3）DNA结合结构域可以识别并结合靶基因调控区中的DNA序列；（4）连接结构域在结构上将DNA结合结构域连接到SH2结构域；（5）STATs的SH2结构域在家族中非常保守，主要功能是识别细胞因子受体的磷酸酪氨酸基序；（6）转录激活结构域对于DNA转录元件和通过保守的丝氨酸磷酸化位点募集共激活因子和调节转录至关重要。

图1 STAT家族的结构、磷酸化位点、活性和非活性形式二聚体

（图片源于《Protein Science》^[1]）

1.2 STATs激活方式

STATs在JAKs下游传递I/II型细胞因子信号。非活性细胞质STATs主要以单体或预先形成的二聚体形式存在。激活的JAKs导致结合受体的酪氨酸磷酸化，形成STATs的停靠位点。在这个停靠位点，JAKs磷酸化STATs，然后STATs与受体解离，并通过SH2结构域-磷酸化酪氨酸相互作用形成同型二聚体或异二聚体。激活后，STATs二聚体形成胡桃夹状结构。高度保守的SH2结构域形成了该结构的铰链，是大多数STATs抑制剂的靶标。然后，这些二聚体转移到细胞核中，诱导启动子含有适当STATs结合位点的基因转录。细胞核中磷酸酶对STATs的去磷酸化使它们能够穿梭回细胞质中，进行下一个轮次的激活。

图2 细胞因子诱导的JAK/STAT通路信号级联示意图

（图片源于《Protein Science》^[1]）

2. STATs与肿瘤的相关研究

越来越多的证据表明，STATs激活与肿瘤进展有关。多项研究表明，STAT1、STAT2、STAT3、STAT4、STAT5、STAT6在白血病、乳腺癌、前列腺癌、结直肠癌、肝癌、肾细胞癌（RCC）等肿瘤中激活^[2-9]。高STATs磷酸化水平与更高的复发风险、肿瘤晚期、静脉浸润、多发性肿瘤结节相关，提示患者预后不良^{[4,5,7,10-14]}。STATs的激活驱动肿瘤的上皮间质转化（EMT）并增强侵袭性和迁移性^[3,7,15-17]。STAT1是HPV阴性头颈部鳞状细胞癌（HNSCC）小鼠模型中放射耐药的介质^[18]。下调STAT1表达可显著提高RCC细胞系的放射敏感性^[8]。STAT5a通过上调ABCB1的转录赋予乳腺癌化疗耐药性^[19]。阻断STAT3和STAT5磷酸化并诱导其降解，可选择性地诱导原代T细胞幼淋巴细胞白血病（T-PLL）中的细胞死亡^[20]。STAT3敲低促进索拉非尼诱导的细胞凋亡，刺激树突状细胞中的cGAS-STING信号通路，从而增强了CD8 T和NK细胞的抗肿瘤功能^[21]。STAT3或STAT5的靶向抑制可诱导骨肉瘤细胞周期停滞和凋亡，并显著抑制小鼠模型中异种移植物的生长^[22,23]。这些发现强调了靶向抑制STATs可能是一种有前景的肿瘤治疗方法。

图3 JPX-1244直接靶向STAT3和STAT5，影响蛋白质磷酸化和稳定性

（图片源于《Leukemia》^[20]）

3. STATs与自身免疫疾病的相关研究

STATs是细胞因子信号通路的核心转录因子家族，其异常激活与多种自身免疫性疾病的发病机制密切相关。在类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、银屑病、干燥综合征、克罗恩病（CD）和溃疡性结肠炎（UC）等多种疾病中，STAT1、STAT2、STAT3、STAT5、STAT6总蛋白及其磷酸化形式的水平升高^[24-36]。STAT4基因内的多个SNP与自身免疫性疾病有很强的遗传关联，与疾病易感性和发展显著相关^[37-39]。抑制STAT1或STAT3可改善RA动物模型中的关节炎症和关节破坏，显著抑制疾病进展^[40,41]。STAT6敲除可减轻小鼠结肠炎模型炎症反应，体重、结肠长度和组织病理学都有所改善^[31]。下调STAT3的表达水平可改善咪喹莫特诱导的银屑病皮肤病变^[42]。STAT5四聚体促进脑膜中Th17细胞和单核细胞衍生细胞之间的相互作用，进而参与实验性自身免疫性脑脊髓炎的发病机制^[43]。这些结果突出了STATs在自身免疫性疾病发病机制中的作用，可能为开发新的治疗方式提供帮助。

4. STATs与心血管疾病

STATs蛋白在心血管疾病中扮演着复杂且关键的角色。暴露于缺血/再灌注（I/R）损伤的心脏细胞经历细胞凋亡，并伴随着STAT1的磷酸化、表达和转录活性的增加^[44]。STAT1过表达的细胞比STAT1缺乏的细胞更容易发生缺血诱导的细胞死亡。在暴露于I/R损伤下，与非转基因同胎（NTG）相比，表达组成型活性STAT3（TG）小鼠心脏的梗死面积减少^[45]。TG心脏在I/R应激反应中产生的ROS程度低于NTG。与Apoe^-/-小鼠相比，高脂饮食（HFD）的STAT4缺乏Stat4^-/-Apoe^-/-小鼠，斑块负担减少，动脉粥样硬化显著减轻^[46]。STAT5抑制剂治疗通过减少炎症显著减轻了HFD诱导的Apoe^-/-小鼠的动脉粥样硬化^[47]。主动脉弓缩窄（TAC）术后，小鼠心脏STAT6活性增加^[48]。与野生型小鼠相比，TAC术后STAT6^-/-小鼠舒张末期左心室内径显著增加，并伴有收缩力受损，表明STAT6对心脏血流动力学应激起保护作用。这些结果提示STATs是心血管疾病中的“双刃剑”，其在心肌保护、动脉粥样硬化、炎症中的积极作用与负面效应并存。

5. STATs与神经退行性疾病

干扰素反应和干扰素刺激基因（ISG）在神经炎症和神经退行性疾病中发挥显著作用。在阿尔茨海默病（AD）中的生物信息学分析显示，Oas1g被鉴定为枢纽基因，与干扰素相关通路密切相关^[49]。siOas1g可以逆转siSTAT1的作用，表明Oas1g可能通过STAT1途径调节ISG。α-突触核蛋白表达通过定位到细胞核、促进STAT2激活、与神经元中的磷酸化STAT2共定位以及促进ISG的表达来支持神经元特异性干扰素反应^[50]。在幽门螺杆菌衍生的条件培养基（HPCM）处理的神经元和神经元-星形胶质细胞共培养的细胞中发现STAT1、STAT3和AD相关蛋白APP和APOE4的表达升高^[51]。STAT3的特异性抑制降低了HPCM诱导的神经元区室中pSTAT3和AD标志物的表达。AD小鼠海马体中IL-6-STAT3和cGAS-STING通路显著激活，STAT3直接调控cGAS和STING基因的转录^[52]。IL-6缺乏通过调节STAT3-cGAS-STING通路来减轻AD小鼠的神经炎症。Aurantiamide（Aur）促进小胶质细胞的M2极化，提高AD小鼠的认知能力，STAT6抑制剂处理可拮抗Aur的作用^[53]。这些数据提示STATs可能是调节神经退行性疾病炎症过程的潜在治疗靶点。

图4 幽门螺杆菌分泌物通过调节STAT3信号通路引发神经炎症和神经变性

（图片源于《Virulence》^[51]）

6. STATs与过敏性疾病

STATs信号通路整合多种关键细胞因子的信号，是过敏性疾病免疫病理机制的核心枢纽。抗原暴露会导致致敏小鼠肺部STAT6和STAT1激活^[54]。鼻内抗T细胞免疫球蛋白和粘蛋白结构域-1（TIM-1）给药通过修复STAT1和STAT6通路来改善哮喘小鼠模型的过敏性肺部炎症和重塑^[55]。Stat1^-/-小鼠经曼氏血吸虫卵抗原（SEA）致敏后，鼻腔嗜酸性细胞受损，组胺诱导的鼻腔高反应性明显降低，提示STAT1参与了小鼠SEA诱导的过敏性鼻炎（AR）的发病机制^[56]。STAT3对于ILC2细胞功能至关重要，并促进ILC2驱动的肺部过敏性炎症^[57]。STAT3缺乏或抑制STAT3线粒体易位显著抑制ILC2过敏反应并改善过敏性肺部炎症。机制分析表明MicroRNA-146a通过积极靶向STAT5b增强AR中的调节性T细胞（Tregs）分化和功能^[58]。STAT6中杂合功能获得变异引起的新的原发性特应性疾病，导致严重的早发性过敏^[59]。深入了解STATs在特定过敏性疾病中的作用，不仅有助于阐明发病机制，也为开发更精准有效的靶向治疗提供坚实的理论基础。

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