Stabilization of hypoxia-inducible factor 1 alpha(HIF1α),which plays a pivotal role in regulating cellular responses to insufficient oxygen,is implicated in cancer progression,particularly epithelial-mesenchymal tran...Stabilization of hypoxia-inducible factor 1 alpha(HIF1α),which plays a pivotal role in regulating cellular responses to insufficient oxygen,is implicated in cancer progression,particularly epithelial-mesenchymal transition and metastatic dissemination.Despite its crucial role in tumorigenesis,the precise mechanisms governing HIF1αstabilization under varying tumor microenvironmental conditions are not fully understood.In this study,we show that stabilization of HIF1αin metastasizing melanoma under mild hypoxia is regulated primarily by mitochondrial reactive oxygen species(ROS)rather than by reduced oxygen levels.Activated HIF1αsuppresses the expression of cyclophilin D(CypD),a regulator of the mitochondrial permeability transition pore(mPTP),as a reciprocal regulatory mechanism to sustain HIF1 signaling via upregulation of microRNAs miR-23a and miR-27a.展开更多
4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of...4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of 4-1BB is responsible for the survival and immune effector functions of T cells.展开更多
The homeostatic balance between effector T cells and regulatory T cells(Tregs)is crucial for adaptive immunity;however,epigenetic programs that inhibit phosphorylation to regulate Treg development,peripheral expressio...The homeostatic balance between effector T cells and regulatory T cells(Tregs)is crucial for adaptive immunity;however,epigenetic programs that inhibit phosphorylation to regulate Treg development,peripheral expression,and suppressive activity are elusive.Here,we found that the Ssu72 phosphatase is activated by various T-cell receptor signaling pathways,including the T-cell receptor and IL-2R pathways,and localizes at the cell membrane.Deletion of Ssu72 in T cells disrupts CD4+T-cell differentiation into Tregs in the periphery via the production of high levels of the effector cytokines IL-2 and IFNγ,which induce CD4+T-cell activation and differentiation into effector cell lineages.We also found a close correlation between downregulation of Ssu72 and severe defects in mucosal tolerance in patients.Interestingly,Ssu72 forms a complex with PLCγ1,which is an essential effector molecule for T-cell receptor signaling as well as Treg development and function.Ssu72 deficiency impairs PLCγ1 downstream signaling and results in failure of Foxp3 induction.Thus,our studies show that the Ssu72-mediated cytokine response coordinates the differentiation and function of Treg cells in the periphery.展开更多
基金supported by a National Research Foundation of Korea(NRF)grantfunded by the Korean government(MSIT)(NRF-2022R1C1C2010351,2022M3E5F2017408,RS-2024-00342382).
文摘Stabilization of hypoxia-inducible factor 1 alpha(HIF1α),which plays a pivotal role in regulating cellular responses to insufficient oxygen,is implicated in cancer progression,particularly epithelial-mesenchymal transition and metastatic dissemination.Despite its crucial role in tumorigenesis,the precise mechanisms governing HIF1αstabilization under varying tumor microenvironmental conditions are not fully understood.In this study,we show that stabilization of HIF1αin metastasizing melanoma under mild hypoxia is regulated primarily by mitochondrial reactive oxygen species(ROS)rather than by reduced oxygen levels.Activated HIF1αsuppresses the expression of cyclophilin D(CypD),a regulator of the mitochondrial permeability transition pore(mPTP),as a reciprocal regulatory mechanism to sustain HIF1 signaling via upregulation of microRNAs miR-23a and miR-27a.
基金This study was supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(2022R1A2C1005463[BKC],2022R1C1C1010078[SHK],and 2022R1C1C1003152[CH]from MSIT)by the National Cancer Center of Korea(NCC)grant funded by the Ministry of Health and Welfare(NCC-2212450[CH]).
文摘4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of 4-1BB is responsible for the survival and immune effector functions of T cells.
基金supported by a National Research Foundation grant funded by the Korean government(MEST)(2017R1A2B3006776).
文摘The homeostatic balance between effector T cells and regulatory T cells(Tregs)is crucial for adaptive immunity;however,epigenetic programs that inhibit phosphorylation to regulate Treg development,peripheral expression,and suppressive activity are elusive.Here,we found that the Ssu72 phosphatase is activated by various T-cell receptor signaling pathways,including the T-cell receptor and IL-2R pathways,and localizes at the cell membrane.Deletion of Ssu72 in T cells disrupts CD4+T-cell differentiation into Tregs in the periphery via the production of high levels of the effector cytokines IL-2 and IFNγ,which induce CD4+T-cell activation and differentiation into effector cell lineages.We also found a close correlation between downregulation of Ssu72 and severe defects in mucosal tolerance in patients.Interestingly,Ssu72 forms a complex with PLCγ1,which is an essential effector molecule for T-cell receptor signaling as well as Treg development and function.Ssu72 deficiency impairs PLCγ1 downstream signaling and results in failure of Foxp3 induction.Thus,our studies show that the Ssu72-mediated cytokine response coordinates the differentiation and function of Treg cells in the periphery.
