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PLoS One. 2009 Nov 24;4(11):e8011. doi: 10.1371/journal.pone.0008011.

Mst1-FoxO signaling protects Naïve T lymphocytes from cellular oxidative stress in mice.

Author information

  • 1Department of Biological Sciences, National Research Laboratory of Molecular Genetics, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.

Abstract

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 gamma-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.

PMID:
19956688
[PubMed - indexed for MEDLINE]
PMCID:
PMC2776980
Free PMC Article

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