國家衛生研究院 NHRI:Item 3990099045/14403
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    题名: MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKK beta and inducing IKK beta-mediated FoxO1 nuclear export and Foxp3 downregulation
    其它题名: MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation
    作者: Chi, JN;Yang, JY;Hsueh, CH;Tsai, CY;Chuang, HC;Tan, TH
    贡献者: Immunology Research Center
    摘要: Rationale: GLK (MAP4K3) activates PKC theta-IKK beta axis in T-cell activation and induces IL-17A-mediated autoimmune diseases. Attenuation of Treg differentiation and function by GLK could also contribute to autoimmune diseases. Methods: We analyzed the roles of GLK and IKK beta in Treg differentiation and function using T-cell-specific GLK transgenic mice and IKK beta conditional knockout mice. The mechanism of GLK/IKK beta-mediated attenuation of Treg differentiation/function was studied by chromatin-immunoprecipitation, reporter assays, in vitro kinase assays, protein-protein interaction assays, mass spectrometry, confocal microscopy, flow cytometry, and single-cell RNA sequencing (scRNA-seq) analysis. Results: We found that GLK signaling inhibited Foxp3 transcription by blocking the function of the transcription factor FoxO1. Mechanistically, GLK directly phosphorylated and activated IKK beta at Ser733 in a PKC theta-independent manner. The phospho-IKK beta Ser733 induced FoxO1 Ser319 phosphorylation and nuclear export, leading to Foxp3 downregulation. Consistently, scRNA-seq analyses showed that Foxp3 mRNA levels were inversely correlated with FoxO1 mRNA levels in GLK transgenic CD4(+) T cells. Conclusions: GLK-IKK beta-FoxO1 signaling axis inhibits Foxp3 transcription, leading to reduction of Treg differentiation and suppressive activity, as well as induction of autoimmune disease.
    日期: 2022-07-18
    關聯: Theranostics. 2022 Jul 18;12(12):5744-5760.
    Link to: http://dx.doi.org/10.7150/thno.72148
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1838-7640&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000829099700017
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85135392973
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