Non-canonical Hippo signaling regulates immune responses.

The Hippo signaling pathway has been shown to play a pivotal role in controlling organ size and maintaining tissue homeostasis in multiple organisms ranging from Drosophila to mammals. Recently, we and others have demonstrated that Hippo signaling is also essential for maintaining the immune system homeostasis. Unlike the canonical Mst-Lats-Yap signal pathway, which controls tissue growth during development and regeneration, most studies regarding Hippo signaling in immune regulation is focusing in Mst1/2, the core kinases of Hippo signaling, cross-talking with other signaling pathways in various immune cells. In particular, patients bearing a loss-of-function mutation of Mst1 develop a complex immunodeficiency syndrome. Regarding the Hippo signaling in innate immunity, we have reported that Mst1/2 kinases are required for phagocytosis and efficient clearance of bacteria in phagocytes by regulating reactive oxygen species (ROS) production; and at the same time, by sensing the excessive ROS, Mst1/2 kinases maintain cellular redox homeostasis and prevent phagocytes aging and death through modulating the stability of the key antioxidant transcription factor Nrf2. In addition, we have revealed that the Mst1/2 kinases are critical in regulating T cells activation and Mst1/2-TAZ axis regulates the reciprocal differentiation of Treg cells and Th17 cells to modulate autoimmune inflammation by altering interactions between the transcription factors Foxp3 and RORγt. These results indicate that Hippo signaling maintains the balance between tolerance and inflammation of adaptive immunity.