Hippo Signal Transduction Mechanisms in T Cell Immunity

Abstract

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 coactivator 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.

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“…For instance, inhibition of PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1 resulted in defective T cell immunity ( Xu et al, 2021 ). Hippo signaling pathway was also involved in T cell immunity ( Bouchard et al, 2020 ) and TGF-beta signaling pathway were known to induce M2-like macrophage polarization ( Gratchev, 2017 ). Above findings could partly explain how DCBLD2 affects the infiltration of immune cells.…”

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“…This is in contrast to FoxO signaling: Akt inhibits whereas Mst promotes nuclear translocation of FoxO proteins. Therefore, the relative strength of Akt and Mst kinase activities in different T cell subsets may highly influence the outcome of β-catenin and FoxO signaling [ 37 ].…”

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“…The conserved Hippo signaling pathway has also been identified as a regulator of iNKT cell development and metabolism. Environmental cues such as cell-to-cell contact activate the conserved Hippo signaling pathway, which blocks cell proliferation by inhibiting the transcription factors Yes-associated protein (YAP) and transcriptional coactivator with PDZ motif (TAZ) [ 27 ]. There are two integral serine/threonine kinases in the mammalian Hippo signaling pathway: Mst1 and Mst2 [ 27 ].…”

“…Environmental cues such as cell-to-cell contact activate the conserved Hippo signaling pathway, which blocks cell proliferation by inhibiting the transcription factors Yes-associated protein (YAP) and transcriptional coactivator with PDZ motif (TAZ) [ 27 ]. There are two integral serine/threonine kinases in the mammalian Hippo signaling pathway: Mst1 and Mst2 [ 27 ]. Mst1 promotes efficient adhesion of lymphocytes to the high endothelial venules, allowing for proper lymphocyte trafficking to lymphoid organs [ 28 ].…”