Mst1-FoxO Signaling Protects Naïve T Lymphocytes from Cellular Oxidative Stress in Mice

Abstract

BackgroundThe Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in Drosophila. In C. elegans, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, Mst1, plays a role in apoptosis induced by various types of apoptotic stress. Mst1 also regulates peripheral naïve T cell trafficking and proliferation in mice. However, its functions in mammals are not fully understood.Methodology/Principal FindingsHere, we report that the Mst1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naïve T cells. In Mst1−/− mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in Mst1−/− T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored Mst1−/− T cell survival. Crossing Mst1 transgenic mice (Mst1 Tg) with Mst1−/− mice reduced ROS levels and restored normal numbers of peripheral naïve T cells in Mst1 Tg;Mst1−/− progeny. Interestingly, peripheral T cells from Mst1−/− mice were hypersensitive to γ-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant.Conclusions/SignificanceThese data support the hypothesis that tolerance to increased levels of intracellular ROS provided by the Mst1-FoxOs signaling pathway is crucial for the maintenance of naïve T cell homeostasis in the periphery.

Asymmetric cancer cell division regulated by AKT

“…Nor do we know whether G0-like cancer cells are enriched in vivo primarily through selection or induction by chemotherapy. However, many factors in the complex tumor microenvironment, including exposure to chemotherapy, modulate AKT signaling, leading us to speculate that AKT modulation (either naturally occurring or pharmacologically induced) may in fact regulate the proportion of G0-like cancer cells within actual human tumors (25,26). Interestingly, two recent reports have identified rare, slowly cycling subpopulations in lung and melanoma cancer cell lines that are drug resistant, but it is unclear whether these cells similarly arise through asymmetric division (27,28).…”

Phosphorylation of SAV1 by mammalian ste20-like kinase promotes cell death

“…Although MST1 is known to activate apoptosis in cell cultures (3,4), MST1-knockout mice showed only a mild phenotype in T cell physiology (5,6). However, the MST1/2 double knockout is embryonic lethal, suggesting a functional redundancy of MST1 and MST2 (7).…”

“…YAP1 is a transcriptional co-activator that is responsible for the expression of multiple apoptosis-related genes (8)(9)(10). MST1, which is activated by oxidative stress phosphorylates FOXO1/3a and inhibits the Akt-induced nuclear exit of FOXO1/3a (5,11,12). Additionally, the MST-induced phosphorylation of histone H2B regulates chromatin compaction during apoptosis (13,14).…”

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

“…Mst1 interacts with a Rap1-binding protein RAPL (Rassf5c) and transmits Rap1-RAPL signals to induce polarized morphology and integrin-dependent lymphocyte adhesion by TCR and chemokines 19 . Mst1-deficient mice generated by gene-targeted or -trapped Mst1 exhibit hypoplastic lymphoid organs because of defective lymphocyte trafficking [20][21][22] . Thymocyte egress in Mst1-deficient mice is also impaired, leading to a modest increase in mature thymocytes 20,21 .…”

“…Recently, mutations in STK4/MST1 have been reported in patients with recurrent infections and autoimmune manifestations with autoantibodies, increased effector-memory subsets and hypergammaglobulinemia G and A 25,26 . The patients exhibited a progressive loss of naive CD4 + T cells, perhaps due to stress-induced apoptosis during severe infections 22 .…”