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

Department of Biological Sciences, National Research Laboratory of Molecular Genetics, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e8011. DOI: 10.1371/journal.pone.0008011
Source: PubMed


The 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.
Here, 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 gamma-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant.
These 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.

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    • "However, further studies of Mst1 deficient T cells demonstrated that Mst1 may be regulating lymphocyte survival by protecting T lymphocytes from cellular oxidative stress and controlling the expression of the IL7 receptor [13], [18]. Mst1 was shown to regulate T cell survival and naive T cell homeostasis in the periphery by activating the FoxO1 and 3 transcriptional factors and their downstream targets, Sod2 and catalase, involved in the regulation of cellular oxidative stress [18]. "
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