Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity

Kim, Won Sam; Kim, Mi Jeong; Kim, Dong Oh; Byun, Jaechul; Huy, Hangsak; Song, Hae Young; Park, Young-Jun; Kim, Tae-Don; Yoon, Suk Ran; Choi, Eun‐Ji; Jung, Hye Young; Choi, Inpyo

doi:10.1038/srep46153

Cited by 39 publications

(35 citation statements)

References 47 publications

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“…This further implies the migration defects of both Raptor- and Rictor-deficient NK cells. Moreover, an increase in the transcript level of Socs2 in Rictor cKO NK cells ( Figure 5C ) may contribute to their impaired proliferation and reduced cellularity ( Kim et al, 2017 ). Related to NK cell effector functions, the RNA sequencing data revealed that Rictor, but not Raptor, deficiency results in reduced transcripts level of Ifng and Gzmb ( Figure 5B and C ).…”

Section: Resultsmentioning

confidence: 99%

mTORC1 and mTORC2 differentially promote natural killer cell development

Yang

Tsaih

Lemke

et al. 2018

eLife

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Natural killer (NK) cells are innate lymphoid cells that are essential for innate and adaptive immunity. Mechanistic target of rapamycin (mTOR) is critical for NK cell development; however, the independent roles of mTORC1 or mTORC2 in regulating this process remain unknown. Ncr1iCre-mediated deletion of Rptor or Rictor in mice results in altered homeostatic NK cellularity and impaired development at distinct stages. The transition from the CD27+CD11b− to the CD27+CD11b+ stage is impaired in Rptor cKO mice, while, the terminal maturation from the CD27+CD11b+ to the CD27−CD11b+ stage is compromised in Rictor cKO mice. Mechanistically, Raptor-deficiency renders substantial alteration of the gene expression profile including transcription factors governing early NK cell development. Comparatively, loss of Rictor causes more restricted transcriptome changes. The reduced expression of T-bet correlates with the terminal maturation defects and results from impaired mTORC2-AktS473-FoxO1 signaling. Collectively, our results reveal the divergent roles of mTORC1 and mTORC2 in NK cell development.

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Section: Resultsmentioning

confidence: 99%

mTORC1 and mTORC2 differentially promote natural killer cell development

Yang

Tsaih

Lemke

et al. 2018

eLife

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“…To elucidate the correlation between TXNIP and AKT, we examined whether TXNIP interacts with AKT in cells. TXNIP‐ and AKT‐overexpressing plasmids were cotransfected into 293T cells, and GST pull‐down assays were performed as previously described (Kim et al, 2017, 2017). TXNIP was found to interact with AKT (Supporting Information Figure S3A), which was also confirmed by immunoprecipitation assays in 293T cells (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

Self Cite

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Aging is associated with an inevitable and universal loss of cell homeostasis and restricts an organism's lifespan by an increased susceptibility to diseases and tissue degeneration. The glucose uptake associated with producing energy for cell survival is one of the major causes of ROS production under physiological conditions. However, the overall mechanisms by which glucose uptake results in cellular senescence remain mysterious. In this study, we found that TXNIP deficiency accelerated the senescent phenotypes of MEF cells under high glucose condition. TXNIP‐/‐ MEF cells showed greater induced glucose uptake and ROS levels than wild‐type cells, and N‐acetylcysteine (NAC) treatment rescued the cellular senescence of TXNIP‐/‐ MEF cells. Interestingly, TXNIP‐/‐ MEF cells showed continuous activation of AKT during long‐term subculture, and AKT signaling inhibition completely blocked the cellular senescence of TXNIP‐/‐ MEF cells. In addition, we found that TXNIP interacted with AKT via the PH domain of AKT, and their interaction was increased by high glucose or H2O2 treatment. The inhibition of AKT activity by TXNIP was confirmed using western blotting and an in vitro kinase assay. TXNIP deficiency in type 1 diabetes mice (Akita) efficiently decreased the blood glucose levels and finally increased mouse survival. However, in normal mice, TXNIP deficiency induced metabolic aging of mice and cellular senescence of kidney cells by inducing AKT activity and aging‐associated gene expression. Altogether, these results suggest that TXNIP regulates cellular senescence by inhibiting AKT pathways via a direct interaction under conditions of glucose‐derived metabolic stress.

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“…SOCS1 even prevents regulatory T (Treg) cells from producing IFN-γ by suppression of STAT1, avoiding the conversion of Treg cells into effector cells ( 106 ). In addition, SOCS2-deficient mice showed a reduction in lung metastases and an increase in survival following melanoma challenge ( 107 ).…”

Section: Canonical Signaling and Regulatory Mechanismsmentioning

confidence: 99%

Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

et al. 2018

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Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient’s survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.

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Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity

Cited by 39 publications

References 47 publications

mTORC1 and mTORC2 differentially promote natural killer cell development

mTORC1 and mTORC2 differentially promote natural killer cell development

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

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