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  • Certainly the immune relevance of Hippo becomes more

    2021-11-24

    Certainly, the immune relevance of Hippo becomes more complicated and divergent in the vertebrates than in Drosophila. In terms of inflammation of mammalians, the stories are diversified (Fig. 2). Previously, MST1/2 has been well characterized not only as a controller of lymphocytes adhesion and migration [[40], [41], [42]], but also as an inhibitor in peripheral immunity through slowing native T cell proliferation and inducing T-regulatory LIMKi 3 (Tregs) differentiation [43,44], which is an effective way to protect the body from suffering autoimmune diseases. As Tregs are born to maintain immune tolerance, it has also been reported that they are recruited by epicardium through Hippo to antagonize the post-infarct inflammatory response [36]. YAP and TAZ are required during this process. They function by modulating the cytokines in the ischemic environment, significantly raising the level of IFN-γ, a cytokine that directly recruits Tregs (Fig. 2a). Epicardial YAP/TAZ–mutant mice even suffered poorer prognosis than the wild-type ones, which reverses the idiomatic image of this “oncoprotein”. In addition to functioning through chemical factor transduction, inflammation also mechanically exerts its effect through a YAP/TAZ-associated manner named mechanotransduction [45]. The alteration of extracellular matrix in a chronic inflammatory environment is correlated with elevated nuclear YAP/TAZ. In light of the evidence that cytoplasmic YAP/TAZ forms into the complex that degrades β-Catenin [46]; the nuclear translocation of YAP/TAZ, on the contrary, increases β-Catenin expression and activates the mechanotransduction pathway, which eventually causes corneal squamous cell metaplasia (Fig. 2b). However, it has been observed that podocyte injury-induced YAP/TAZ activation thickens and stiffens the basement membrane in the rigid substrate, resulting in glomerular diseases in mice [47]. Even though the detailed mechanisms are still under delineation, it has been believed that fibrotic-like process is responsible for the changes of the extracellular matrix, in which a diversity of immunocytes and cytokines are involved [45]. Analogous to pathogen invasion in Drosophila, YAP-CTGF axis was suggested to be stimulated in mammals by helminth infection, which wakens an anti-parasite immune response known as intestinal epithelial cell turnover (Fig. 2c). This response was weakened when YAP-TEADs interaction was disrupted, which made the host more susceptible to the pathogens [48]. On the other hand, while facing viral infection, Zhang Q's team has indicated a novel mechanism of Hippo [49]. Exogenous DNA or RNA deriving from virus activate TBK1 signaling, which induces adaptive immunity to clear the pathogens; however, Hippo will repress this strong antiviral inflammation when the growth condition of cells is improved. Sufficient nutrient inactivates LATS1/2, allowing the released YAP/TAZ to bind and disable TBK1 (Fig. 2d). More importantly, rather than wading into the immune-associated cascades directly, inflammation-activated Hippo leads cellular growth to counter inflammation itself, which makes Hippo more dedicated to its initial duty. For instance, a group of scientists has well elucidated that YAP activation was triggered by IL-6 in mammalian cells [50]. Under these circumstances, when facing the damage brought by an inflammatory reaction, this YAP-dependent self-renewal mechanism is launched in cultured embryonic stem cells (Fig. 2e). However, the related processes in vivo have yet to be charted. Owing to the wide existence of raised IL-6 in numerous chronic inflammatory contexts and cancers, it is reasonable to speculate that this IL-6-induced YAP activation might be a general event among mammalian cells [51].
    Hippo in YAP-driven cancerous immunity The microenvironment of inflammation incites detrimental mutations, breeding various chances for tumorigenesis. Within this environment, there are full of dynamic interplays between immune cells and cancer cells (Fig. 3) [52,53]. Macrophages behave actively among those immune cells, during which they protect those cancerous cells from immune clearance with the help of activated YAP [54]. In fact, this occurs in an early phase when there is only a singular tumor-initiating cell (TIC). The widely embraced concept of notorious oncoprotein YAP comes from the fact that excessive activation of YAP in any stage of carcinogenesis [55], especially in terms of those cancer types that mainly depend on the dysfunction of Hippo-YAP axis, which is also known as YAP-dependent carcinogenesis [54,[56], [57], [58]]. Aside from facilitating to escape from size controlling, the newly unveiled idea is that YAP-TEAD complex also increases chemokines and growth factors, which in turn recruits macrophages to abolish immune surveillance and eliminate tumor-initiating cell (Fig. 3a). For the first time, this remarkable work from Guo X et al. has well illustrated the immunological importance of Hippo at the beginning stage of cancer progression [54].