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


RESULTS
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
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.
Choi
Juhyun
J
Department of Biological Sciences, National Research Laboratory of Molecular Genetics, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Oh
Sangphil
S
Lee
Dongjun
D
Oh
Hyun Jung
HJ
Park
Jik Young
JY
Lee
Sean Bong
SB
Lim
Dae-Sik
DS
D000818:Animals; D017209:Apoptosis; D002374:Catalase / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018384:Oxidative Stress; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D002374:Catalase; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D017228:Hepatocyte Growth Factor; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C467200:Foxo1 protein, mouse; C082332:macrophage stimulating protein