[HTML][HTML] Mst1-FoxO signaling protects Naive T lymphocytes from cellular oxidative stress in mice

J Choi, S Oh, D Lee, HJ Oh, JY Park, SB Lee, DS Lim - PloS one, 2009 - journals.plos.org
PloS one, 2009journals.plos.org
Background 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. Methodology/Principal Findings Here, we report that the Mst1-FoxO signaling …
Background
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.
Methodology/Principal Findings
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 γ-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant.
Conclusions/Significance
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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