Related Experiment Video
Updated: Jun 18, 2026
Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe
Published on: September 17, 2021
Mst1-FoxO signaling protects Naïve T lymphocytes from cellular oxidative stress in mice
Juhyun Choi1, Sangphil Oh, Dongjun Lee
1Department of Biological Sciences, National Research Laboratory of Molecular Genetics, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
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.
Insights
The Mst1-FoxO pathway is vital for naive T cell survival by managing reactive oxygen species (ROS). Mst1 deficiency impairs this pathway, leading to T cell loss and hypersensitivity to oxidative stress.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- The Ste-20 family kinase Hippo regulates cell proliferation and apoptosis in Drosophila.
- Mammalian Ste20-like protein kinase 1 (Mst1) is involved in stress-induced apoptosis and T cell regulation.
- The precise functions of Mst1 in mammals remain incompletely understood.
Purpose of the Study:
- To investigate the role of the Mst1-FoxO signaling pathway in naive T cell survival.
- To elucidate the mechanisms by which Mst1 influences T cell homeostasis.
Main Methods:
- Utilized Mst1 knockout (Mst1(-/-)) and transgenic (Mst1 Tg) mouse models.
- Assessed FoxO activation, protein levels, and downstream targets (Sod2, catalase) in T cells.
- Evaluated intracellular reactive oxygen species (ROS) levels and T cell sensitivity to oxidative stress.
Main Results:
- Mst1 deficiency led to impaired FoxO activation, decreased FoxO levels, and reduced expression of FoxO targets Sod2 and catalase in naive T cells.
- Mst1(-/-) T cells exhibited elevated ROS levels and increased apoptosis, with impaired survival.
- Restoration of FoxO3a or Mst1 expression mitigated ROS levels and normalized peripheral naive T cell numbers.
- Mst1(-/-) T cells showed hypersensitivity to oxidative stress, while Mst1 Tg T cells were resistant.
Conclusions:
- The Mst1-FoxO signaling pathway is critical for naive T cell survival, not apoptosis.
- This pathway confers tolerance to increased intracellular ROS, maintaining peripheral naive T cell homeostasis.
- Mst1 plays a key role in protecting naive T cells from oxidative damage.
