| First Author | Chi JN | Year | 2022 |
| Journal | Theranostics | Volume | 12 |
| Issue | 13 | Pages | 5744-5760 |
| PubMed ID | 35966593 | Mgi Jnum | J:346793 |
| Mgi Id | MGI:7331150 | Doi | 10.7150/thno.72148 |
| Citation | Chi JN, et al. (2022) MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKbeta and inducing IKKbeta-mediated FoxO1 nuclear export and Foxp3 downregulation. Theranostics 12(13):5744-5760 |
| abstractText | Rationale: GLK (MAP4K3) activates PKCtheta-IKKbeta 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 IKKbeta in Treg differentiation and function using T-cell-specific GLK transgenic mice and IKKbeta conditional knockout mice. The mechanism of GLK/IKKbeta-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 IKKbeta at Ser733 in a PKCtheta-independent manner. The phospho-IKKbeta 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-IKKbeta-FoxO1 signaling axis inhibits Foxp3 transcription, leading to reduction of Treg differentiation and suppressive activity, as well as induction of autoimmune disease. |
