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

• Published in: PloS one 2009-11, Vol.4 (11), p.e8011-e8011
• Main Authors: Choi, Juhyun, Oh, Sangphil, Lee, Dongjun, Oh, Hyun Jung, Park, Jik Young, Lee, Sean Bong, Lim, Dae-Sik
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Catalase; Catalase - metabolism; Cell activation; Cell Biology; Cell Biology/Cell Signaling; Cell Biology/Cellular Death and Stress Responses; Cell Proliferation; Cell Survival; Drosophila; Forkhead Box Protein O1; Forkhead protein; Forkhead Transcription Factors - metabolism; FOXO1 protein; FOXO3 protein; Genetic crosses; Hepatocyte Growth Factor - metabolism; Homeostasis; Homology; Humans; Immunological tolerance; Intracellular; Intracellular signalling; Irradiation; Kinases; Lymphocytes; Lymphocytes T; Mammals; Mice; Mice, Transgenic; Models, Biological; Oxidation resistance; Oxidative Stress; Oxygen; Paraquat; Progeny; Protein kinase; Proto-Oncogene Proteins - metabolism; Radiation; Reactive Oxygen Species; Rodents; Saccharomyces cerevisiae; Science; Signal Transduction; Superoxide dismutase; Superoxide Dismutase - metabolism; Survival; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transgenic mice
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008011

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.