STAT家族蛋白：細(xì)胞命運(yùn)的“指揮官”，疾病發(fā)展的關(guān)鍵推手

1. STAT家族簡(jiǎn)介

信號(hào)傳導(dǎo)子和轉(zhuǎn)錄激活子（STAT）家族是一類(lèi)關(guān)鍵的細(xì)胞內(nèi)蛋白，充當(dāng)細(xì)胞質(zhì)信號(hào)傳導(dǎo)分子和核轉(zhuǎn)錄因子的雙重角色。當(dāng)細(xì)胞因子、生長(zhǎng)因子或激素等信號(hào)分子與細(xì)胞表面受體結(jié)合后，STATs就會(huì)被激活。激活的STATs形成二聚體，轉(zhuǎn)運(yùn)到細(xì)胞核內(nèi)，直接結(jié)合特定DNA序列，調(diào)控靶基因的表達(dá)，從而介導(dǎo)細(xì)胞增殖、分化、存活、免疫應(yīng)答和炎癥等多種重要的細(xì)胞過(guò)程。

1.1 STAT家族結(jié)構(gòu)

STATs是JAKs下游的信號(hào)分子。哺乳動(dòng)物中有7個(gè)STAT家族成員（STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B和STAT6），它們?cè)诟鞣N生理和病理過(guò)程中扮演著獨(dú)特且有時(shí)重疊的角色。STATs由750-900個(gè)氨基酸組成。從N端到C端，由N端結(jié)構(gòu)域、卷曲螺旋結(jié)構(gòu)域、DNA結(jié)合結(jié)構(gòu)域、連接結(jié)構(gòu)域、SH2結(jié)構(gòu)域和轉(zhuǎn)錄激活結(jié)構(gòu)域組成。六個(gè)結(jié)構(gòu)域調(diào)節(jié)STATs的不同功能：（1）N端結(jié)構(gòu)域促進(jìn)STATs二聚體的形成，從而使其能夠與轉(zhuǎn)錄因子結(jié)合；（2）卷曲螺旋結(jié)構(gòu)域與調(diào)節(jié)蛋白有關(guān)，并參與STATs核導(dǎo)入和導(dǎo)出過(guò)程的控制；（3）DNA結(jié)合結(jié)構(gòu)域可以識(shí)別并結(jié)合靶基因調(diào)控區(qū)中的DNA序列；（4）連接結(jié)構(gòu)域在結(jié)構(gòu)上將DNA結(jié)合結(jié)構(gòu)域連接到SH2結(jié)構(gòu)域；（5）STATs的SH2結(jié)構(gòu)域在家族中非常保守，主要功能是識(shí)別細(xì)胞因子受體的磷酸酪氨酸基序；（6）轉(zhuǎn)錄激活結(jié)構(gòu)域?qū)τ?/span>DNA轉(zhuǎn)錄元件和通過(guò)保守的絲氨酸磷酸化位點(diǎn)募集共激活因子和調(diào)節(jié)轉(zhuǎn)錄至關(guān)重要。

圖1 STAT家族的結(jié)構(gòu)、磷酸化位點(diǎn)、活性和非活性形式二聚體

（圖片源于《Protein Science》^[1]）

1.2 STATs激活方式

STATs在JAKs下游傳遞I/II型細(xì)胞因子信號(hào)。非活性細(xì)胞質(zhì)STATs主要以單體或預(yù)先形成的二聚體形式存在。激活的JAKs導(dǎo)致結(jié)合受體的酪氨酸磷酸化，形成STATs的停靠位點(diǎn)。在這個(gè)?？课稽c(diǎn)，JAKs磷酸化STATs，然后STATs與受體解離，并通過(guò)SH2結(jié)構(gòu)域-磷酸化酪氨酸相互作用形成同型二聚體或異二聚體。激活后，STATs二聚體形成胡桃?jiàn)A狀結(jié)構(gòu)。高度保守的SH2結(jié)構(gòu)域形成了該結(jié)構(gòu)的鉸鏈，是大多數(shù)STATs抑制劑的靶標(biāo)。然后，這些二聚體轉(zhuǎn)移到細(xì)胞核中，誘導(dǎo)啟動(dòng)子含有適當(dāng)STATs結(jié)合位點(diǎn)的基因轉(zhuǎn)錄。細(xì)胞核中磷酸酶對(duì)STATs的去磷酸化使它們能夠穿梭回細(xì)胞質(zhì)中，進(jìn)行下一個(gè)輪次的激活。

圖2 細(xì)胞因子誘導(dǎo)的JAK/STAT通路信號(hào)級(jí)聯(lián)示意圖

（圖片源于《Protein Science》^[1]）

2. STATs與腫瘤的相關(guān)研究

越來(lái)越多的證據(jù)表明，STATs激活與腫瘤進(jìn)展有關(guān)。多項(xiàng)研究表明，STAT1、STAT2、STAT3、STAT4、STAT5、STAT6在白血病、乳腺癌、前列腺癌、結(jié)直腸癌、肝癌、腎細(xì)胞癌（RCC）等腫瘤中激活^[2-9]。高STATs磷酸化水平與更高的復(fù)發(fā)風(fēng)險(xiǎn)、腫瘤晚期、靜脈浸潤(rùn)、多發(fā)性腫瘤結(jié)節(jié)相關(guān)，提示患者預(yù)后不良^{[4,5,7,10-14]}。STATs的激活驅(qū)動(dòng)腫瘤的上皮間質(zhì)轉(zhuǎn)化（EMT）并增強(qiáng)侵襲性和遷移性^[3,7,15-17]。STAT1是HPV陰性頭頸部鱗狀細(xì)胞癌（HNSCC）小鼠模型中放射耐藥的介質(zhì)^[18]。下調(diào)STAT1表達(dá)可顯著提高RCC細(xì)胞系的放射敏感性^[8]。STAT5a通過(guò)上調(diào)ABCB1的轉(zhuǎn)錄賦予乳腺癌化療耐藥性^[19]。阻斷STAT3和STAT5磷酸化并誘導(dǎo)其降解，可選擇性地誘導(dǎo)原代T細(xì)胞幼淋巴細(xì)胞白血?。?/span>T-PLL）中的細(xì)胞死亡^[20]。STAT3敲低促進(jìn)索拉非尼誘導(dǎo)的細(xì)胞凋亡，刺激樹(shù)突狀細(xì)胞中的cGAS-STING信號(hào)通路，從而增強(qiáng)了CD8 T和NK細(xì)胞的抗腫瘤功能^[21]。STAT3或STAT5的靶向抑制可誘導(dǎo)骨肉瘤細(xì)胞周期停滯和凋亡，并顯著抑制小鼠模型中異種移植物的生長(zhǎng)^[22,23]。這些發(fā)現(xiàn)強(qiáng)調(diào)了靶向抑制STATs可能是一種有前景的腫瘤治療方法。

圖3 JPX-1244直接靶向STAT3和STAT5，影響蛋白質(zhì)磷酸化和穩(wěn)定性

（圖片源于《Leukemia》^[20]）

3. STATs與自身免疫疾病的相關(guān)研究

STATs是細(xì)胞因子信號(hào)通路的核心轉(zhuǎn)錄因子家族，其異常激活與多種自身免疫性疾病的發(fā)病機(jī)制密切相關(guān)。在類(lèi)風(fēng)濕性關(guān)節(jié)炎（RA）、系統(tǒng)性紅斑狼瘡（SLE）、銀屑病、干燥綜合征、克羅恩?。?/span>CD）和潰瘍性結(jié)腸炎（UC）等多種疾病中，STAT1、STAT2、STAT3、STAT5、STAT6總蛋白及其磷酸化形式的水平升高^[24-36]。STAT4基因內(nèi)的多個(gè)SNP與自身免疫性疾病有很強(qiáng)的遺傳關(guān)聯(lián)，與疾病易感性和發(fā)展顯著相關(guān)^[37-39]。抑制STAT1或STAT3可改善RA動(dòng)物模型中的關(guān)節(jié)炎癥和關(guān)節(jié)破壞，顯著抑制疾病進(jìn)展^[40,41]。STAT6敲除可減輕小鼠結(jié)腸炎模型炎癥反應(yīng)，體重、結(jié)腸長(zhǎng)度和組織病理學(xué)都有所改善^[31]。下調(diào)STAT3的表達(dá)水平可改善咪喹莫特誘導(dǎo)的銀屑病皮膚病變^[42]。STAT5四聚體促進(jìn)腦膜中Th17細(xì)胞和單核細(xì)胞衍生細(xì)胞之間的相互作用，進(jìn)而參與實(shí)驗(yàn)性自身免疫性腦脊髓炎的發(fā)病機(jī)制^[43]。這些結(jié)果突出了STATs在自身免疫性疾病發(fā)病機(jī)制中的作用，可能為開(kāi)發(fā)新的治療方式提供幫助。

4. STATs與心血管疾病

STATs蛋白在心血管疾病中扮演著復(fù)雜且關(guān)鍵的角色。暴露于缺血/再灌注（I/R）損傷的心臟細(xì)胞經(jīng)歷細(xì)胞凋亡，并伴隨著STAT1的磷酸化、表達(dá)和轉(zhuǎn)錄活性的增加^[44]。STAT1過(guò)表達(dá)的細(xì)胞比STAT1缺乏的細(xì)胞更容易發(fā)生缺血誘導(dǎo)的細(xì)胞死亡。在暴露于I/R損傷下，與非轉(zhuǎn)基因同胎（NTG）相比，表達(dá)組成型活性STAT3（TG）小鼠心臟的梗死面積減少^[45]。TG心臟在I/R應(yīng)激反應(yīng)中產(chǎn)生的ROS程度低于NTG。與Apoe^-/-小鼠相比，高脂飲食（HFD）的STAT4缺乏Stat4^-/-Apoe^-/-小鼠，斑塊負(fù)擔(dān)減少，動(dòng)脈粥樣硬化顯著減輕^[46]。STAT5抑制劑治療通過(guò)減少炎癥顯著減輕了HFD誘導(dǎo)的Apoe^-/-小鼠的動(dòng)脈粥樣硬化^[47]。主動(dòng)脈弓縮窄（TAC）術(shù)后，小鼠心臟STAT6活性增加^[48]。與野生型小鼠相比，TAC術(shù)后STAT6^-/-小鼠舒張末期左心室內(nèi)徑顯著增加，并伴有收縮力受損，表明STAT6對(duì)心臟血流動(dòng)力學(xué)應(yīng)激起保護(hù)作用。這些結(jié)果提示STATs是心血管疾病中的“雙刃劍”，其在心肌保護(hù)、動(dòng)脈粥樣硬化、炎癥中的積極作用與負(fù)面效應(yīng)并存。

5. STATs與神經(jīng)退行性疾病

干擾素反應(yīng)和干擾素刺激基因（ISG）在神經(jīng)炎癥和神經(jīng)退行性疾病中發(fā)揮顯著作用。在阿爾茨海默病（AD）中的生物信息學(xué)分析顯示，Oas1g被鑒定為樞紐基因，與干擾素相關(guān)通路密切相關(guān)^[49]。siOas1g可以逆轉(zhuǎn)siSTAT1的作用，表明Oas1g可能通過(guò)STAT1途徑調(diào)節(jié)ISG。α-突觸核蛋白表達(dá)通過(guò)定位到細(xì)胞核、促進(jìn)STAT2激活、與神經(jīng)元中的磷酸化STAT2共定位以及促進(jìn)ISG的表達(dá)來(lái)支持神經(jīng)元特異性干擾素反應(yīng)^[50]。在幽門(mén)螺桿菌衍生的條件培養(yǎng)基（HPCM）處理的神經(jīng)元和神經(jīng)元-星形膠質(zhì)細(xì)胞共培養(yǎng)的細(xì)胞中發(fā)現(xiàn)STAT1、STAT3和AD相關(guān)蛋白APP和APOE4的表達(dá)升高^[51]。STAT3的特異性抑制降低了HPCM誘導(dǎo)的神經(jīng)元區(qū)室中pSTAT3和AD標(biāo)志物的表達(dá)。AD小鼠海馬體中IL-6-STAT3和cGAS-STING通路顯著激活，STAT3直接調(diào)控cGAS和STING基因的轉(zhuǎn)錄^[52]。IL-6缺乏通過(guò)調(diào)節(jié)STAT3-cGAS-STING通路來(lái)減輕AD小鼠的神經(jīng)炎癥。Aurantiamide（Aur）促進(jìn)小膠質(zhì)細(xì)胞的M2極化，提高AD小鼠的認(rèn)知能力，STAT6抑制劑處理可拮抗Aur的作用^[53]。這些數(shù)據(jù)提示STATs可能是調(diào)節(jié)神經(jīng)退行性疾病炎癥過(guò)程的潛在治療靶點(diǎn)。

圖4 幽門(mén)螺桿菌分泌物通過(guò)調(diào)節(jié)STAT3信號(hào)通路引發(fā)神經(jīng)炎癥和神經(jīng)變性

（圖片源于《Virulence》^[51]）

6. STATs與過(guò)敏性疾病

STATs信號(hào)通路整合多種關(guān)鍵細(xì)胞因子的信號(hào)，是過(guò)敏性疾病免疫病理機(jī)制的核心樞紐?？乖┞稌?huì)導(dǎo)致致敏小鼠肺部STAT6和STAT1激活^[54]。鼻內(nèi)抗T細(xì)胞免疫球蛋白和粘蛋白結(jié)構(gòu)域-1（TIM-1）給藥通過(guò)修復(fù)STAT1和STAT6通路來(lái)改善哮喘小鼠模型的過(guò)敏性肺部炎癥和重塑^[55]。Stat1^-/-小鼠經(jīng)曼氏血吸蟲(chóng)卵抗原（SEA）致敏后，鼻腔嗜酸性細(xì)胞受損，組胺誘導(dǎo)的鼻腔高反應(yīng)性明顯降低，提示STAT1參與了小鼠SEA誘導(dǎo)的過(guò)敏性鼻炎（AR）的發(fā)病機(jī)制^[56]。STAT3對(duì)于ILC2細(xì)胞功能至關(guān)重要，并促進(jìn)ILC2驅(qū)動(dòng)的肺部過(guò)敏性炎癥^[57]。STAT3缺乏或抑制STAT3線(xiàn)粒體易位顯著抑制ILC2過(guò)敏反應(yīng)并改善過(guò)敏性肺部炎癥。機(jī)制分析表明MicroRNA-146a通過(guò)積極靶向STAT5b增強(qiáng)AR中的調(diào)節(jié)性T細(xì)胞（Tregs）分化和功能^[58]。STAT6中雜合功能獲得變異引起的新的原發(fā)性特應(yīng)性疾病，導(dǎo)致嚴(yán)重的早發(fā)性過(guò)敏^[59]。深入了解STATs在特定過(guò)敏性疾病中的作用，不僅有助于闡明發(fā)病機(jī)制，也為開(kāi)發(fā)更精準(zhǔn)有效的靶向治療提供堅(jiān)實(shí)的理論基礎(chǔ)。

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