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Hans Journal of Biomedicine
Vol. 12  No. 02 ( 2022 ), Article ID: 50535 , 10 pages
10.12677/HJBM.2022.122017

Hippo信号通路与人类免疫调控的研究进展

苟洪伟，吴夏俊鹏，王莹，赵铁军，辛晓茹*

浙江师范大学化学与生命科学学院，浙江 金华

收稿日期：2022年3月10日；录用日期：2022年4月17日；发布日期：2022年4月22日

摘要

Hippo信号是与器官大小调控、组织再生和肿瘤发展密切相关的信号通路。最近，越来越多的研究表明Hippo信号通路还在人类免疫调控中发挥重要作用。在本文中，我们主要总结了Hippo信号通路的组成及其调控机制，以及Hippo信号网络中的各种组分在人类免疫系统中的作用，重点介绍了Hippo通路在先天免疫以及抗肿瘤免疫方面的重要调节功能。本文为Hippo通路相关领域研究，以及免疫相关致病机制和治疗策略提供了新的思路。

关键词

Hippo信号通路，YAP/TAZ，免疫，肿瘤

Research Progress of Hippo Signaling Pathway and Human Immune Regulation

Hongwei Gou, Xiajunpeng Wu, Ying Wang, Tiejun Zhao, Xiaoru Xin*

College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua Zhejiang

Received: Mar. 10th, 2022; accepted: Apr. 17th, 2022; published: Apr. 22nd, 2022

ABSTRACT

The hippo signaling pathway is closely related to organ size regulation, tissue regeneration and tumor development. Recently, more and more studies have shown that Hippo signaling pathway also plays an important role in human immune regulation. In this paper, we mainly summarize the composition and regulatory mechanism of Hippo signaling pathway, and the roles of various components of Hippo signaling network in human immune system, focusing on the important regulatory functions of Hippo pathway in innate immunity and anti-tumor immunity. This paper provides a new idea for the study of Hippo pathway and immune-related pathogenesis and treatment strategies.

Keywords:Hippo Signaling Pathway, YAP/TAZ, Immunity, Tumor

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

Hippo信号通路对细胞外信号做出响应，在组织内稳态、器官再生和肿瘤发生中起关键作用。Hippo通路最初在果蝇中被发现，它在进化过程中高度保守。这一信号通路的发现始于一种肿瘤抑制基因(Wts)的发现而受到关注。Wts基因的突变导致细胞形态以及增殖出现异常 [1] [2]。随后的研究中发现，Sav (Salvador)基因突变后与Wts突变体具有相似的表型，它可以通过其WW结构域而与Wts发生结合 [3] [4]。Hippo基因(Hpo)被发现位于Wts基因的上游，Hpo基因的缺失使果蝇头部组织过度生长而形似“河马”的头部，因此这一相关途径被称为“Hippo信号通路” [5] [6]。后来的研究发现了Hippo信号通路中的另一个肿瘤抑制因子Mob (Mats)，Mats同样能与Wts相互作用而激活Hpo信号 [7]。Yorkie (Yki)和Scalloped (Sd)是Hippo通路中重要的转录因子 [8] [9]。所有这些参与调控细胞增殖的基因即组成了经典的Hippo信号通路。这一信号通路在哺乳动物系统中也是保守的。哺乳动物的STE20样蛋白1/2 (MST1/2)和辅因子SAV1 (Human Salvadorhomology 1)、大肿瘤抑制激酶1/2 (LATS1/2)和辅因子MOB1 (MOB kinase activator1 A/B)、以及转录共激活因子YAP (Yes-associated protein)和TAZ (transcriptional co-activator with PDZ binding motif)组成了哺乳动物中的Hippo信号通路 [10] [11] [12]。自Wts基因被发现以来，Hippo通路因参与肿瘤的发生和发展而被广泛关注，并为寻找治疗癌症的靶点提供了新的视角 [13] [14]。

越来越多的研究报道显示Hippo通路的多个核心成分参与调节了人类先天免疫相关的多条信号通路，而这些信号途径同样也能调控Hippo通路。有研究报道，许多免疫缺陷症状，以及细菌和病毒感染，都与Hippo信号传导的缺陷有关 [15]。这些结果促进了人们对Hippo信号通路研究兴趣的激增。然而，Hippo通路在免疫信号中的调控作用仍有待进一步的研究及总结。在文本中我们主要讨论了Hippo信号通路对人类免疫系统调节的研究进展。

2. Hippo信号通路的组成及调控

Hippo通路主要由三个部分组成，包括了上游调节蛋白、核心激酶和下游转录因子和共调节因子。YAP/TAZ蛋白是Hippo信号传导的最终效应物。当Hippo通路被激活时，MST1/2分别在Thr183和Thr180位被磷酸化，进而启动一系列级联激酶信号的传递。被激活的MST1/2与SAV1发生结合并诱导SAV1和MOB1 A/B磷酸化。随后，MST1/2和MOB1 A/B促进LATS1/2的Thr1071和Thr1079位残基磷酸化。紧接着，磷酸化的LATS1/2分别使YAP和TAZ的Ser127和Ser89位残基发生磷酸化。磷酸化的YAP/TAZ与细胞质内的胞质滞留蛋白14-3-3发生结合，使得YAP/TAZ被截留在细胞质 [12] [16] [17]，或被CK1δ/ε (Casein kinase 1 δ/ε)进一步磷酸化，在b-TrCP (β-transducin repeat-containing protein)的诱导下进行泛素化，并以蛋白酶体依赖的方式走向降解 [18] [19]，最终导致YAP/TAZ的生物学功能被抑制。相反，当上游激酶模块“关闭”(Hippo通路“失活”)时，失活的MATS1/2和LATS1/2不能够继续磷酸化YAP/TAZ，而未磷酸化的YAP/TAZ移位进入细胞核内聚集，随后与TEAD1-4家族(Transcriptional enhancer factors 1-4/TEF1-4)发生结合，诱导CTGF，CYR61等促进细胞增殖的靶基因转录 [20] [21] [22] [23] (图1)。

Figure 1. The composition and regulation of Hippo signaling pathway

图1. Hippo信号通路组成及其调控

随着研究的深入，越来越多的调控因子被研究发现参与了Hipoo信号网络的调节。如RASSF5/Nore1B (Ras association domain family member 5/Nore1B)、NDR1/2 (nuclear Dbf2-related 1)、MAP4Ks (mitogen-activated protein kinase kinase kinase kinase)、NF2 (Neurofibromatosis type II)。MAP4K可直接磷酸化和激活LATS1/2，或通过激活激酶NDR1/2替代LATS1/2磷酸化YAP。NDR1/2被MST1/2磷酸化并激活，并使YAP磷酸化导致其失活 [24] [25]。NF2和RASSF5位于MST的上游，NF2响应细胞接触等刺激信号，并促进MST1/2对LATS1/2的磷酸化。RASSF5是MST1/2的上游调节因子，RASSF5通过与MST1/2形成复合物诱导MST1/2的同源二聚化、反式自磷酸化和活化 [26] [27] (图1)。

3. Hipoo通路在先天免疫和获得性免疫中的调控作用

先天免疫存在于免疫细胞和非免疫细胞中，是抵御外来病原体入侵的第一道防线，有助于维持体内生理稳态和获得性免疫反应的激活。宿主通过PAMPs (pathogen associated molecular patterns)这一相关分子模式识别病原体触发先天免疫反应的激活，并启动一系列级联信号的传递，随后通过RIG-I/MDA5或cGAS-STING信号途径将刺激信号聚集在先天免疫途径中心的几种蛋白激酶上。包括TBK1 (TANK-binding kinase 1)、IKKε (IkB kinase e)、IRAK1/2/4 (IL-1R-associated kinase 1/2/4)，以及由IKKa、IKKb和NEMO组成的IKK复合物(NF-κB essential modifier, also known as IKKγ)。其中激活的TBK1/IKKe磷酸化IRF3，导致IRF3二聚化并转移到细胞核中，与活化的NF-κB协同诱导IFN-Is (Type I interferons)和下游ISGs (干扰素刺激基因)、以及炎性细胞因子和趋化因子的产生 [28] [29]。最终，宿主通过这些病毒限制因子建立起强有力的免疫屏障并调节适应性免疫。

近年来，越来越多的证据表明，Hippo通路的多个核心成分参了先天免疫反应的调控。首先在先天免疫细胞方面，巨噬细胞和DCs (dendritic cells)是连接先天免疫和适应性免疫的关键。在肝癌细胞中，YAP激活后导致TICs (Tumor-initiating cells)能够募集M2巨噬细胞或促进M1样巨噬细胞的迁移和浸润 [30] [31]。而在正常肝细胞中MST1/2基因的缺失上调了MCP1 (Monocyte chemotactic protein-1)的表达，导致M1和M2混合表型的巨噬细胞大量浸润，从而促进了HCC (Hepatocellular carcinoma)的发展 [32]。同时Guo等人 [30] 还发现CYR61在肝细胞中充当YAP/TAZ的下游因子诱导肝巨噬细胞的浸润，从而导致肝炎和肝纤维化。Du等人 [33] 发现在DCs中特异性缺失MST1/2后会导致CD8α+T细胞的稳态和功能的选择性破坏。此外，在CD4+T细胞中，MST1通过直接磷酸化Foxo1/3来增强其稳定，并通过减弱TCR诱导的AKT在外周血T细胞中的激活来间接增强Foxo1/3的稳定性，促进Foxp3的表达和Treg细胞(regulatory T cell)的发育，并抑制自身免疫 [34]。Li等人 [35] 报道MST1抑制DCs中IL-6的分泌，间接的抑制了TH17 (CD4+T helper cell)的分化。Treg与TH17之间的不平衡是自身免疫和癌症免疫逃逸的重要因素。这些研究发现表明Hippo通路以独立于其经典的调控方式参与调控了先天免疫细胞的分化和功能。

最近的研究表明YAP/TAZ是先天抗病毒反应的负调控因子，能够有效抑制IFN-Is的产生和上游信号的传导，以及NF-κB的激活。例如，Zhang [36] 等人报道YAP/TAZ直接靶向TBK1阻碍了TBK1 K63多泛素化进而抑制TBK1的激活。同时YAP阻碍了TBK1与MAVS、STING和IRF3的相互作用，最终减少了病毒诱导的IFN-I和ISG的产生。随后在斑马鱼的体内实验中发现，YAP突变体(YAP 6SA)以不依赖于其转录活性的方式抑制先天抗病毒免疫反应、致使斑马鱼胚胎死亡率增加以及增强病毒的复制。而当YAP/TAZ基因敲除或通过LATS1/2激酶使YAP/TAZ失活后，可减弱YAP/TAZ对TBK1的抑制，从而增强抗病毒免疫反应。而在另一项研究中，MST1能直接磷酸化IRF3的T75、T253位残基，阻碍IRF3的二聚化，从而抑制先天抗病毒免疫反应的激活 [37]。相反地，活化的IRF3能够与MST1的启动子结合进而诱导MST1的转录 [38]。与之相似，Jiao [39] 等人研究报道IRF3是YAP的激动剂。在胃癌组织中IRF3的表达与YAP及其靶基因的表达呈正相关。IRF3与YAP和TEAD4在细胞核内相互作用，以增强YAP与TEAD4之间的相互作用，促进YAP的入核和激活。而在通过敲除或药物靶向抑制IRF3后，以YAP依赖的方式抑制胃肿瘤的生长(图1)。此后不久，Wang [40] 等人发现YAP4可以与先天免疫中的关键转录因子IRF3相互作用，并阻止其二聚化和入核，导致IFN-b和ISG的产生减少而增强病毒的感染。随后，在小鼠的体内实验中发现YAP基因缺失后增强了先天抗病毒反应并降低了对病毒的易感性。此外，他们的研究同时发现病毒感染后激活的IKKε诱导了YAP的溶酶体依赖性降解。在机制上，IKKe诱导YAP Ser403位点磷酸化并诱导YAP走向溶酶体依赖性降解。而IKKε基因缺失或YAP S403的突变(YAP S403A)则不能触发YAP的磷酸化和降解。IKKε介导的YAP降解减轻了YAP对先天抗病毒免疫反应的抑制。与YAP4具有相似结构的TAZ变变体cTAZ (缺乏TEAD结合域(TBD)和WW结构域)被报道能与STAT1结合，抑制STAT1/2的二聚化和入核，从而抑制ISGs的表达和抗病毒反应 [41]。最近报道显示，Hippo通路的上游刺激因子NDR2能够促进RIG-I介导的抗病毒免疫反应。NDR2通过直接与RIG-I和TRIM25发生结合，促进RIG-I/TRIM25复合物的形成并增强TRIM25介导的K63连接的多泛素化 [42] (图2)。

总之，这些研究结果表明Hippo通路从不同角度参与调控先天抗病毒免疫，而不同病毒模型以及感染时间可能会影响观察结果，因而需要进一步的研究阐明Hippo与先天免疫之间的联系。

Figure 2. The regulatory role of Hippo signaling pathway in innate immunity

图2. Hippo信号通路在先天免疫中的调控作用

4. Hippo通路在癌症和肿瘤免疫中的调控作用

免疫细胞是存在于肿瘤内的一种重要的非肿瘤性细胞。肿瘤浸润淋巴细胞在决定肿瘤的命运中起着关键作用，并可对癌症的发展施加选择性压力。相反，癌细胞可以操纵免疫细胞的功能形成肿瘤免疫逃逸。YAP/TAZ被研究证明在多种人类恶性肿瘤中过度激活。近年来，Hippo信号通路对肿瘤免疫的调控也受到高度关注。研究发现LATS1/2缺失的肿瘤细胞分泌富含核酸的胞外囊泡，以依赖于Toll-like受体(TLR)-MYD88/TRIF途径的方式诱导I型干扰素的应答，提高了肿瘤细胞的免疫原性，进而通过增强抗肿瘤免疫反应来抑制小鼠皮下移植肿瘤的生长 [43]。与之相反，在肝TICs细胞(Tumor-initiating cells)中，LATS1/2和MST1/2的缺失，导致YAP被激活。活化的YAP通过诱导细胞因子CCL2和CSF的表达来募集肿瘤浸润的II型(M2)巨噬细胞，进而建立免疫抑制，形成免疫逃逸，最终诱发HCC (Hepatocellular carcinoma)的发生 [30] [32]。相比之下，敲低CCL2和CSF1会阻止巨噬细胞募集，解除免疫抑制，导致YAP激活的TICs被免疫系统识别而被清除，最终降低了HCC发生的机率 [30]。激活的YAP还能通过MCP1 (Monocyte chemotactic proteins-1)诱导M1/M2巨噬细胞的极化，从而导致大量巨噬细胞浸润和HCC的发展 [32]。此外，Hagenbeek [44] 等人研究发现TAZ的过度活化能够诱导大量骨髓细胞浸润肝脏，并通过TEAD依赖的方式分泌促炎细胞因子。MDSCs (myeloid-derived suppressor cells)也是一种重要的髓系来源免疫抑制细胞。Wang [45] 等人在鼠前列腺腺癌模型中发现过度激活的YAP能诱导CXCL5的表达上调。CXCL5与其同源受体CXCR2结合促进对MDSC的招募，随后将MDSC引导至肿瘤部位。而药物抑制CXCR2可以阻碍肿瘤的进展。随后，Murakami [46] 等人在PDAC (pancreatic ductal adenocarcinoma)中报道了类似的观察结果。YAP诱导多种细胞因子/趋化因子的表达和分泌，进而促进了体内外MDSC的分化和积累，而特异性敲除YAP或抗体介导的MDSCs缺失可促进巨噬细胞重编程和T细胞重新活化，从而增强抗癌免疫力。此外，研究发现YAP1在PRKCI癌基因下游发挥作用，在卵巢癌小鼠模型中YAP1上调TNFα的表达，并招募MDSC和抑制CTL (cytotoxic T cell)的功能，从而促进形成免疫抑制的肿瘤微环境 [47]。在人类卵巢癌中，PRKCI的高表达也与TNFα和YAP1的高表达以及CTL的低浸润有关 [47]。

综上，这些发现表明，癌细胞中Hippo信号不仅能影响肿瘤生长，而且通过对肿瘤微环境的调节以影响抗肿瘤免疫反应，这也为治疗癌症提供了新的治疗靶点。

5. Hippo通路在抗细菌免疫反应中的调控作用

TLR介导了广泛的抗微生物反应。Liu [48] 等人证明Hippo信号调控了果蝇幼虫脂肪体免疫器官内的先天免疫反应。他们的研究表明果蝇脂肪体中Hippo通路的沉默或Yorkie的激活导致“catus”基因的表达增加，从而导致NF-κB信号的转导、D1 (Dorsal)和Dif (Dorsal-related immune factor)的表达受到抑制、以及抗菌肽表达减少而易受革兰氏阳性菌的感染。另一研究表明嗜肺军团菌感染后可以通过其效应激酶LegK7模拟宿主的MST1激酶来触发YAP/TAZ的降解，导致哺乳动物巨噬细胞中受TAZ调控的转录因子PPARγ的靶基因表达发生改变，抑制巨噬细胞的抗菌免疫反应，最终促进细菌生长和感染 [49]。此外，Hippo通路的其他核心成分同样参与了先天抗菌免疫调节。TLR1，TLR2和TLR4是哺乳动物识别细菌和真菌感染的主要传感器。LPS (TLR4的激动剂)、Pam3CSK4 (TLR1/2的激动剂)或LTA (TLR2的激动剂)能够在BMDM (Bone marrow derived macrophages)中诱导MOB1 A/B的磷酸化，表明TLR信号传导能够激活MST1/2。研究显示，MST1和MST2激酶通过调节线粒体运输和线粒体-吞噬小体来控制ROS (reactive oxygen species)的产生。在TLR激活后，MST1和MST2激活GTPase Rac，以促进TLR诱导的TRAF6-ECSIT复合物的组装，这是吞噬小体吸收线粒体ROS所必须需的。而非激活的Rac，包括人类Rac2 (D57N)突变体，通过隔离TRAF6破坏TRAF6-ECSIT复合体，导致ROS的产生减少，进而增强对细菌感染的易感性。这一研究结果表明，TLR-MST1/2Rac-TRAF6信号传导对于ROS的产生和杀菌活性至关重要 [50]。此外，Boro [51] 等人研究发现结核分枝杆菌在感染期间以依赖于TLR2-IRAK1/4 (interleukin receptor-1 associated kinases)信号轴的方式激活MST1/2。激活的MST1/2独立于LATS1调节IRF3、CXCL1/2的表达和宿主的免疫反应。综上，这些观察表明Hippo通路在先天抗菌免疫中的重要且复杂的调控作用。

6. Hippo通路在细胞内其他免疫相关信号途径中的调控作用

Hippo/YAP信号通路的调控非常复杂。除了其自身的调控外，还能与细胞内其它免疫相关的信号途径进行交叉调控。已知，mTOR被研究报道参与调节了pDCs (plasmacytoid dendritic cells)中TLR介导的IFN-a/b (interferona/b)的产生 [52]。Tumaneng [53] 等人研究报道YAP能激活哺乳动物mTOR (mammalian target of rapamycin)。机制上，YAP通过诱导miR-29与PI3K-mTOR途径相互作用抑制PTEN的翻译，增强mTOR的活性并增强蛋白质的翻译，从而调控细胞的大小。Hippo通路与PI3K-mTOR信号途径(影响蛋白质合成和细胞大小)之间的这种协调产生了强大的协同作用，以调节组织的生长和再生。此外，Gan [54] 等人报道Hippo通路的核心成分LATS1/2能在S606位点磷酸化mTORC1途径中的Raptor，阻碍了Raptor与Rheb的相互作用，从而减弱mTORC1的激活。

Wnt/b-catenin信号途径在调节肿瘤微环境和免疫细胞浸润中发挥重要作用 [55]。Varelas [56] 等发现Hippo通路通过其下游转录因子TAZ与DVL (Dishevelled)发生互作，抑制CK1δ/e介导的DVL的磷酸化，从而抑制Wnt/b-Catenin信号转导。相应地，TAZ或Hippo信号通路的缺失增强了Wnt3A刺激的DVL磷酸化、核b-Catenin和Wnt靶基因表达。随后的一项研究表明YAP/TAZ直接与b-Catenin结合，阻止其入核，从而抑制Wnt靶基因的表达。在人类结直肠癌中，Hippo信号的下调与b-Catenin信号的上调呈负相关 [57]。

NF-κB通常与活化的IRF3协调诱导IFN-I的产生，从而调节细胞免疫反应 [58]。最近，我们小组的研究发现YAP的转录活性在HTLV-1感染细胞和ATL患者中显著增强。在机制上，Tax通过NF-κB/p65通路激活YAP蛋白。随后p65抑制了YAP与LATS1之间的相互作用，导致了YAP磷酸化的抑制，以及抑制了YAP的泛素化依赖降解，从而促进YAP的核积累。相应地，在YAP基因缺失后抑制了ATL细胞的体外增殖和ATL小鼠皮下移植瘤的形成。我们的这一研究结果对p65诱导的YAP激活在ATL发病机制中至关重要，这提示了YAP可能是ATL潜在的治疗靶点 [59]。细胞的信号网络错综复杂，随着研究的进展，Hippo被发现在细胞的多条信号都存在一定程度上的相互调控，尤其与肿瘤发生发展相关的信号途径，因而进一步的研究阐明Hipoo与其它信号交互影响的潜在机制可能会增强对肿瘤治疗的理解。

7. 总结与展望

Hippo信号通路最初在果蝇中被发现，它在决定细胞命运、组织动态平衡和器官发育中发挥重要作用。最近，越来越多的研究表明Hippo信号通路也与人类免疫调节息息相关。本文主要概括了Hippo通路的组成及其多个核心组分在人类免疫中的调控作用。旨在阐明Hippo通路与免疫系统之间的串扰调节，这将有助于设计和开发潜在的抗感染和治疗自身免疫性疾病的药物，以及通过控制Hippo通路进行肿瘤免疫治疗。

尽管当前我们在Hippo通路和免疫系统的理解方面取得了很大进展，但仍然还有许多关键问题有待进一步研究阐明。如在大多数情况下Hippo信号的激活能增强先天免疫反应，相反地，活化的IRF3同样也能激活YAP的功能，而敲除或药理作用抑制IRF3则会以YAP依赖的方式抑制肿瘤的生长 [36] [39]。这提示了这两种信号中的一种信号对另一种信号有正面或负面的调节作用，这可能涉及一种自我保护的正/负反馈调节机制，以避免某一信号的通路的过度激活。总之，Hippo信号与细胞内多种免疫相关信号之间的相互作用是错综复杂的。虽然目前有较多的证据表明Hippo与多种肿瘤免疫的调节相关，但某些情况下似乎存在相互矛盾之处。因此，需要更进一步的研究确认Hippo信号的各种功能和机制。这将有助于拓宽我们对Hippo信号通路与免疫系统之间相互作用的认识。

致谢

我们感谢为这篇文章作出贡献的每一个人。

利益冲突

所有作者均声明不存在利益冲突。

作者贡献声明

苟洪伟：采集并分析数据，撰写文章；吴夏俊鹏：采集数据并审阅；王莹：审阅；赵铁军，辛晓茹：撰写文章，科研经费支持。

基金项目

本研究得到了浙江省自然科学基金(LQ21C060003)和国家自然科学基金项目(31970173)的支持。

文章引用

苟洪伟,吴夏俊鹏,王 莹,赵铁军,辛晓茹. Hippo信号通路与人类免疫调控的研究进展
Research Progress of Hippo Signaling Pathway and Human Immune Regulation[J]. 生物医学, 2022, 12(02): 132-141. https://doi.org/10.12677/HJBM.2022.122017

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    60. NOTES

    *通讯作者。

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