Hippo signaling pathways are evolutionarily conserved signal transduction mechanisms mainly involved in organ size control, tissue regeneration, and tumor suppression. However, in mammals, the primary role of Hippo signaling seems to be regulation of immunity. As such, humans with null mutations in STK4 (mammalian homologue of Drosophila Hippo; also known as MST1) suffer from recurrent infections and autoimmune symptoms. Although dysregulated T cell homeostasis and functions have been identified in MST1-deficient human patients and mouse models, detailed cellular and molecular bases of the immune dysfunction remain to be elucidated. Although the canonical Hippo signaling pathway involves transcriptional co-activator Yes-associated protein (YAP) or transcriptional coactivator with PDZ motif (TAZ), the major Hippo downstream signaling pathways in T cells are YAP/TAZ-independent and they widely differ between T cell subsets. Here we will review Hippo signaling mechanisms in T cell immunity and describe their implications for immune defects found in MST1-deficient patients and animals. Further, we propose that mutual inhibition of Mst and Akt kinases and their opposing roles on the stability and function of forkhead box O and β-catenin may explain various immune defects discovered in mutant mice lacking Hippo signaling components. Understanding these diverse Hippo signaling pathways and their interplay with other evolutionarily-conserved signaling components in T cells may uncover molecular targets relevant to vaccination, autoimmune diseases, and cancer immunotherapies.

中文翻译：

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T 细胞免疫中的河马信号转导机制

Hippo 信号通路是进化上保守的信号转导机制，主要涉及器官大小控制、组织再生和肿瘤抑制。然而，在哺乳动物中，Hippo 信号传导的主要作用似乎是调节免疫。因此，在 STK4（河马果蝇的哺乳动物同源物；也称为 MST1）中具有无效突变的人类会遭受反复感染和自身免疫症状。尽管已经在 MST1 缺陷型人类患者和小鼠模型中发现了失调的 T 细胞稳态和功能，但免疫功能障碍的详细细胞和分子基础仍有待阐明。尽管典型的 Hippo 信号通路涉及转录共激活因子 Yes 相关蛋白 (YAP) 或具有 PDZ 基序的转录共激活因子 (TAZ)，T 细胞中主要的 Hippo 下游信号通路不依赖于 YAP/TAZ，并且它们在 T 细胞亚群之间存在很大差异。在这里，我们将回顾 T 细胞免疫中的 Hippo 信号传导机制，并描述它们对 MST1 缺陷患者和动物中发现的免疫缺陷的影响。此外，我们提出 Mst 和 Akt 激酶的相互抑制及其对 forkhead box O 和 β-catenin 稳定性和功能的相反作用可以解释在缺乏 Hippo 信号成分的突变小鼠中发现的各种免疫缺陷。了解这些不同的 Hippo 信号通路及其与 T 细胞中其他进化保守的信号成分的相互作用，可能会发现与疫苗接种、自身免疫疾病和癌症免疫疗法相关的分子靶标。