br Hippo Signaling in Autoimmunity

Hippo Signaling in Autoimmunity An imbalance of T cell subsets, such as immunosuppressive regulatory T Veratridine (Treg) and inflammatory TH17, has a key role in autoimmune diseases. Recently, investigations found that TAZ but not YAP enhances TH17 differentiation but attenuates Treg differentiation [10]. Mechanistically, TAZ coactivates the TH17-defining transcription factor RORγt while promoting the degradation of the Treg-defining transcription factor Foxp3 (Figure 1B). As a result, KO of TAZ in T cells ameliorates TH17-mediated autoimmune diseases in mouse models. MST1/2 are known to regulate T cell functions, for example, the MST1 mutation in humans was found to cause a primary immunodeficiency syndrome with a progressive loss of naïve T cells, recurrent bacterial and viral infections, and autoimmune manifestations 11, 12. Importantly, TAZ KO attenuates the ability of MST1-deficient T cells to induce intestinal inflammation [10]. Therefore, deregulation of TAZ could underlie autoimmune manifestations caused by MST1 deficiency. In addition, the function of TAZ in directing T cell differentiation is independent of TEADs, which are canonical Hippo pathway transcription factors. Instead, expression of TEAD1 sequesters TAZ away from RORγt, thus repressing TH17 differentiation [10]. Furthermore, the proliferation of T cells is not affected by TAZ KO [10]. Therefore, the Hippo pathway regulates T cell differentiation through a transcriptional program distinct from that in growth control, which might be determined by the expression levels of target transcription factors.
Implications in Therapy Design An additional consideration is that the Hippo pathway functions not only in cancer cells, but also in immune cells. Therefore, mechanisms of the Hippo pathway in innate immunity may also have a role in cancer immunity. Indeed, it was found that inflammatory conditions repress the expression of MST1 in liver macrophages, promoting inflammation, fibrosis, and tumorigenesis [13]. Furthermore, although discussed only in the context of autoimmunity [10], the function of TAZ in directing T cell differentiation may also have a role in shaping the tumor microenvironment. Therefore, the effect of a proposed therapy on different cell types in the tumor microenvironment should be considered. A particular opportunity to enhance effectiveness and to avoid potential adverse effects lies in the differential involvement of YAP, TAZ, and their binding transcription factors in growth control and certain types of immune reactions, for instance, TAZ-TEAD in cancer stem cells and TAZ-RORγt in T cell differentiation [10].
Concluding Remarks
Introduction The liver generally maintains an appropriate size relative to the rest of the body (Forbes and Newsome, 2016, Taub, 2004). How the liver knows when to begin or stop growing is a fundamental unanswered question in liver development, regeneration, and cancer biology. The recently discovered Hippo pathway plays a critical role in controlling organ size and homeostasis in many organisms from Drosophila to mammals (Harvey et al., 2013, Moya and Halder, 2016, Pan, 2010, Yu et al., 2015). Central to this pathway is a kinase cascade formed by the kinases Mst1 and Mst2 (Mst1/2, mammalian ortholog of Hippo), upstream regulators including NF2/Merlin, scaffolding protein Salvador/WW45, downstream NDR family kinases Lats1 and Lats2 (Lats1/2), and adaptor protein Mob1. Mst1/2 phosphorylates and activates Lats1/2-Mob1, which then phosphorylates Yap and its paralog Taz. Phospho-Yap/Taz is either degraded or sequestered in the cytoplasm by the 14-3-3 protein. When the Hippo pathway is off, Yap/Taz translocates to the nucleus and forms a functional hybrid transcriptional factor with TEAD to turn on pro-proliferative and pro-survival genes, thereby enabling cell proliferation. We and others have previously demonstrated that the genetic disruption of kinases Mst1/2 or the Yap transgene results in sustained liver growth, leading to the development of liver cancer within 5 months (Camargo et al., 2007, Dong et al., 2007, Lee et al., 2010, Lu et al., 2010, Song et al., 2010, Wu et al., 2015, Zhang et al., 2017, Zhou et al., 2009). Although kinases Mst1/2 could be regulated by Raf or other upstream factors (Avruch et al., 2012, O'Neill et al., 2004, Romano et al., 2014), the potential identity of extracellular ligands and their cognate receptors that regulate the Hippo pathway remains elusive. Recently, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) have been shown to activate heterotrimeric Gs protein α-subunit (Gαs)-coupled signals to repress Yap/Taz activity through their corresponding G protein-coupled receptors (GPCRs) (Yu and Guan, 2013). Moreover, the GPCR-mediated Yap/Taz activity occurs independent of Mst1/2 kinases. However, liver-specific deletion of GNAS encoding Gαs, which functions as a key molecular switch to transmit various GPCR signals to inhibit cell growth (He et al., 2014, Iglesias-Bartolome et al., 2015), did not result in enlarged liver sizes or phenocopy the effect of Yap overexpression (Chen et al., 2004). These findings indicate that GPCR signaling alone is not capable or is insufficient to induce Yap/Taz activity for liver size control. Thus, the external sensing or signaling factors that modulate the Hippo signaling cascade to restrain liver growth and oncogenesis remain unidentified.