Hippo信号通路是在进化上高度保守的调控器官大小和维持组织稳态的重要信号通路.早期研究多集中于经典的Hippo信号通路调控器官发育、组织再生和肿瘤发生发展.近年来多项研究发现,以Mst1/2(Ste20-like kinases 1/2)为核心的非经典Hippo信号通路通过与其他信号转导通路的协同互作来调控免疫应答和功能,从而在维持免疫系统稳态中发挥重要作用.本文重点阐述本研究团队在非经典Hippo信号通路调控天然免疫细胞抗感染、维持氧化还原稳态、响应微环境硬度及T细胞分化等方面的研究进展.
Background: The Hippo pathway is an evolutionarily conserved pathway that governs organ size and maintains tissue homeostasis. Early studies mostly focused on the canonical Hippo signaling pathway, Ste20-like kinase-large tumor suppressors-Yes-associated protein (Mst-Lats-YAP), which regulates tissue development, regeneration, and tumor development. The function of Hippo signaling is to inhibit the activation of the transcriptional coactivator YAP, which accelerates proliferation, inhibits apoptosis and causes massive organ overgrowth through interaction with transcriptional enhanced associate domain (TEAD) transcription factors in the nucleus. In general, Mst1/2 associates with the WW-domain scaffold protein WW45 and phosphorylate Lats1/2. Lats1/2 kinases phosphorylate the YAP and promote the binding of 14-3-3 protein to YAP, leading to YAP nuclear exit and thus inhibiting its function. In recent years, many studies have shown that Hippo signaling also regulates immune responses. In particular, Mst1-null mice and patients bearing loss-of-function mutations of Mst1 both exhibit a combined immunodeficiency symptoms characterized by recurrent bacterial or viral infections, T or B cell lymphopenia and autoimmune diseases. More and more studies have revealed that the non-canonical Hippo pathway which focuses on Mst1/2 kinases, functions through synergistic interaction with other signal transduction pathways in immune cells and plays an important role in maintaining the homeostasis of the immune system.
Progress: This review focuses on our group’s research progress on the non-classical Hippo signaling pathway in both innate and adaptive immunity. In response to bacterial infection, TLR drives the innate immune response through the mechanical sensor Piezo1 to activate calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)-Mst1/2-Rac (small G protein) signaling axis for effective phagocytic induction of reactive oxygen species (ROS) and bactericidal activity. At the same time, the kinases Mst1/2 sense ROS and maintain cellular redox balance by modulating the stability of antioxidant transcription factor, nuclear factor erythroid2-related factor 2(Nrf2), in innate immune cells. Our studies revealed that Mst1/2 act as a molecular switch to maintain redox homeostasis by coordinating induction of ROS to kill microbes and clearance excess ROS to attenuate oxidative stress in macrophages. In addition, we also found that Mst1/2 kinases are critical in regulating T cell activation and differentiation. The inflammatory Th17 subset of helper T cells plays a critical role in autoimmunity and tissue damage, whereas the immunosuppressive regulatory T (Treg) cells are essential for mediating immune tolerance and immunosuppressive. The dysregulation of Th17 and Treg cells is often linked with several immune diseases. Our recent study revealed that Mst1/2 kinases and their downstream effector, the transcriptional coactivator TAZ, regulate the reciprocal differentiation of Th17 and Treg cells for modulating the development of autoimmune and/or inflammatory diseases.
Perspective: The Hippo pathway regulates cellular proliferation and survival to maintain the tissue homeostasis during development and prevent cancer development. Recent findings demonstrate that Hippo signaling also plays a critical role in regulating immune homeostasis, suggesting that the Hippo signaling pathway might act as a potential therapeutic target in infection diseases, autoimmune diseases and immune cells ageing. However, these findings might raise new concerns about the current thought on Hippo signaling as a target for cancer treatment. Thus, the alternative network of Hippo signaling involved in immune regulation and in tumor development remains to be further explored. We expect that new insights into regulating Hippo signaling under physiological or pathological conditions will be beneficial to the design and development of potential therapeutic agents for multiple diseases.
