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

ABSTRACT: 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 blockin

SUBMITTER: Chi JN 

PROVIDER: S-EPMC9373822 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature