Theranostics 2022; 12(13):5744-5760. doi:10.7150/thno.72148 This issue Cite

Research Paper

MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation

Jyun-Ni Chi1,§, Jhih-Yu Yang1,§, Chia-Hsin Hsueh1,§, Ching-Yi Tsai1, Huai-Chia Chuang1,✉, Tse-Hua Tan1,2,✉

1. Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.
2. Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA.
§These authors contributed equally to this work.

Citation:
Chi JN, Yang JY, Hsueh CH, Tsai CY, Chuang HC, Tan TH. MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation. Theranostics 2022; 12(13):5744-5760. doi:10.7150/thno.72148. https://www.thno.org/v12p5744.htm
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Abstract

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Rationale: GLK (MAP4K3) activates PKCθ-IKKβ 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 IKKβ in Treg differentiation and function using T-cell-specific GLK transgenic mice and IKKβ conditional knockout mice. The mechanism of GLK/IKKβ-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 IKKβ at Ser733 in a PKCθ-independent manner. The phospho-IKKβ 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-IKKβ-FoxO1 signaling axis inhibits Foxp3 transcription, leading to reduction of Treg differentiation and suppressive activity, as well as induction of autoimmune disease.

Keywords: MAP4K3/GLK, FoxO1, IKKβ, Foxp3, Treg


Citation styles

APA
Chi, J.N., Yang, J.Y., Hsueh, C.H., Tsai, C.Y., Chuang, H.C., Tan, T.H. (2022). MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation. Theranostics, 12(13), 5744-5760. https://doi.org/10.7150/thno.72148.

ACS
Chi, J.N.; Yang, J.Y.; Hsueh, C.H.; Tsai, C.Y.; Chuang, H.C.; Tan, T.H. MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation. Theranostics 2022, 12 (13), 5744-5760. DOI: 10.7150/thno.72148.

NLM
Chi JN, Yang JY, Hsueh CH, Tsai CY, Chuang HC, Tan TH. MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation. Theranostics 2022; 12(13):5744-5760. doi:10.7150/thno.72148. https://www.thno.org/v12p5744.htm

CSE
Chi JN, Yang JY, Hsueh CH, Tsai CY, Chuang HC, Tan TH. 2022. MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation. Theranostics. 12(13):5744-5760.

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