Mst1-FoxO Signaling Protects Naïve T Lymphocytes from Cellular Oxidative Stress in Mice

Department of Biological Sciences, National Research Laboratory of Molecular Genetics, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e8011. DOI: 10.1371/journal.pone.0008011
Source: PubMed


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.

Download full-text


Available from: Sean Bong Lee,
  • Source
    • "However, further studies of Mst1 deficient T cells demonstrated that Mst1 may be regulating lymphocyte survival by protecting T lymphocytes from cellular oxidative stress and controlling the expression of the IL7 receptor [13], [18]. Mst1 was shown to regulate T cell survival and naive T cell homeostasis in the periphery by activating the FoxO1 and 3 transcriptional factors and their downstream targets, Sod2 and catalase, involved in the regulation of cellular oxidative stress [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1-/- B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1-/- CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.
    PLoS ONE 05/2014; 9(5):e98151. DOI:10.1371/journal.pone.0098151 · 3.23 Impact Factor
  • Source
    • "Though many transcription factors have been identified, the three clock-controlled TF families which control the functions of all of the patterns through binding sites on non-clock controlled TFs are FKHD, KLFS, and STAT (Figure 3). The FKHD transcription factor family includes the Fox-O transcription factor, which is well known for its protective role against oxidative stress within the body [48]. Similarly, KLFS is well known for its role in the regulation of anti polymicrobial bacteria activity within the body and metabolism in liver [25,49], while STAT has already been identified as a critical transcription factor during the outcome of sepsis [50]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The circadian clock is a critical regulator of biological functions controlling behavioral, physiological and biochemical processes. Because the liver is the primary regulator of metabolites within the mammalian body and the disruption of circadian rhythms in liver is associated with severe illness, circadian regulators would play a strong role in maintaining liver function. However, the regulatory structure that governs circadian dynamics within the liver at a transcriptional level remains unknown. To explore this aspect, we analyzed hepatic transcriptional dynamics in Sprague-Dawley rats over a period of 24 hours to assess the genome-wide responses. Using an unsupervised consensus clustering method, we identified four major gene expression clusters, corresponding to central carbon and nitrogen metabolism, membrane integrity, immune function, and DNA repair, all of which have dynamics which suggest regulation in a circadian manner. With the assumption that transcription factors (TFs) that are differentially expressed and contain CLOCK:BMAL1 binding sites on their proximal promoters are likely to be clock-controlled TFs, we were able to use promoter analysis to putatively identify additional clock-controlled TFs besides PARF and RORA families. These TFs are both functionally and temporally related to the clusters they regulate. Furthermore, we also identified significant sets of clock TFs that are potentially transcriptional regulators of gene clusters. All together, we were able to propose a regulatory structure for circadian regulation which represents alternative paths for circadian control of different functions within the liver. Our prediction has been affirmed by functional and temporal analyses which are able to extend for similar studies.
    BMC Bioinformatics 03/2014; 15(1):83. DOI:10.1186/1471-2105-15-83 · 2.58 Impact Factor
  • Source
    • "Lim’s group recently also shows that Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis [33]. In the immune system, Mst1 deficient peripheral T cells have impaired FOXO1/3 and decreased FOXO protein levels indicating a crucial role of the Mst1-FOXO signaling pathway for the maintenance of naive T cell homeostasis [34]. Mst1 deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis [35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hippo signaling pathway has emerged as a critical regulator for organ size control. The serine/threonine protein kinases Mst1 and Mst2, mammalian homologs of the Hippo kinase from Drosophila, play the central roles in the Hippo pathway controlling the cell proliferation, differentiation, and apoptosis during development. Mst1/2 can be activated by cellular stressors and the activation of Mst1/2 might enforce a feedback stimulation system to regulate oxidant levels through several mechanisms, in which regulation of cellular redox state might represent a tumor suppressor function of Mst1/2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in multiple organs, although considerable diversification in the pathway composition and regulation is observed in some of them. Generally, loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by the reduction or elimination of YAP. The Hippo pathway integrates with other signaling pathways e.g. Wnt and Notch pathways and coordinates with them to impact on the tumor pathogenesis and development. Furthermore, Mst1/2 kinases also act as an important regulator in immune cell activation, adhesion, migration, growth, and apoptosis. This review will focus on the recent updates on those aspects for the roles of Mst1/2 kinases.
    Cell and Bioscience 08/2013; 3(1):31. DOI:10.1186/2045-3701-3-31 · 3.63 Impact Factor
Show more