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MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function.

ABSTRACT: BACKGROUND:Foxp3+CD4+ regulatory T cells (Treg) constitutes a key event in autoimmune diseases. STAT5b is the critical link between the IL-2/15 and FOXP3, the master regulator of Treg cells. METHODS:The CD3+T cell and Foxp3+CD4+ regulatory T cells were overexpressioned or knockdown MKL-1 and STAT5a and tested for Treg cell development and function. Direct interaction of MKL-1 and STAT5a were analyzed by coimmunoprecipitation assays, Luciferase assay, Immunofluoresence Staining and Yeast two-hybrid screening. The effect of MKL-1 and STAT5a on the Treg genes expression was analyzed by qPCR and western blotting and Flow cytometry. RESULTS:However, the molecular mechanisms mediating STAT5b-dependent Treg genes expression and Treg cell phenotype and function in autoimmune diseases are not well defined. Here, we report that the MKL-1 is a coactivator for the major Treg genes transcription factor STAT5b, which is required for human Treg cell phenotype and function. The N terminus of STAT5b, which contains a basic coiled-coil protein-protein interaction domain, binds the C-terminal activation domain of MKL-1 and enhances MKL-1 mediated transcriptional activation of Treg-specific, CArG containing promoters, including the Treg-specific genes Foxp3. Suppression of endogenous STAT5b expression by specific small interfering RNA attenuates MKL-1 transcriptional activation in cultured human cells. The STAT5b-MKL-1 interaction identifies a role of Treg-specific gene regulation and regulated mouse Treg cell development and function and suggests a possible mechanism for the protective effects of autoimmune disease Idiopathic Thrombocytopenic Purpura (ITP). CONCLUSIONS:Our studies demonstrate for the first time that MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function. Video abstract.

SUBMITTER: Xiang Y

PROVIDER: S-EPMC7350762 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function.

Xiang Yuan Y Wang Jun J Li Jia Peng JP Guo Wei W Huang Feng F Zhang Hui Min HM Li Han Han HH Dai Zhou Tong ZT Zhang Zi Jian ZJ Li Hui H Bao Le Yuan LY Gu Chao Jiang CJ Chen Kun K Zhang Tong Cun TC Liao Xing Hua XH

Cell communication and signaling : CCS 20200709 1

<h4>Background</h4>Foxp3<sup>+</sup>CD4<sup>+</sup> regulatory T cells (Treg) constitutes a key event in autoimmune diseases. STAT5b is the critical link between the IL-2/15 and FOXP3, the master regulator of Treg cells.<h4>Methods</h4>The CD3<sup>+</sup>T cell and Foxp3<sup>+</sup>CD4<sup>+</sup> regulatory T cells were overexpressioned or knockdown MKL-1 and STAT5a and tested for Treg cell development and function. Direct interaction of MKL-1 and STAT5a were analyzed by coimmunoprecipitation a ...[more]

PMID: 32646440

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Project description:BackgroundProtein phosphates 4 (PP4), encoded by the ppp4c gene, is a ubiquitously expressed phosphatase that has been implicated in the regulation of cytokine signaling and lymphocyte survival; recent reports suggest that PP4 may be involved in pre-TCR signaling and B cell development. However, whether PP4 also modulates the functions of peripheral T cells has not been investigated due to the lack of a suitable in vivo model. Treg cells are a specialized subset of CD4 helper T cells that can suppress the proliferation of activated effector T cells. In the absence of this negative regulation, autoimmune syndromes and inflammatory diseases, such as human Crohn's disease, will arise.ResultsIn this report, we generated mice with T cell-specific ablation of the ppp4c gene (CD4cre:PP4(f/f)) and a Foxp3-GFP reporter gene to examine the roles of PP4 in Treg development and function. Characterizations of the CD4cre:PP4(f/f) mice showed that PP4 deficiency induced partial αβ T lymphopenia and T cell hypo-proliferation. Further analyses revealed significant reductions in the numbers of thymic and peripheral Treg cells, as well as in the efficiency of in vitro Treg polarization. In addition, PP4-deficient Treg cells exhibited reduced suppressor functions that were associated with decreased IL-10, CTLA4, GITR and CD103 expression. More interestingly, the CD4cre:PP4(f/f) mice developed spontaneous rectal prolapse and colitis with symptoms similar to human Crohn's disease. The pathogenesis of colitis required the presence of commensal bacteria, and was correlated with reduced Treg cells in the gut. Nevertheless, PP4-deficient Treg cells were still capable of suppressing experimental colitis, suggesting that multiple factors contributed to the onset of the spontaneous colitis.ConclusionsWhile the molecular mechanisms remain to be investigated, our results clearly show that PP4 plays a non-redundant role for the differentiation, suppressor activity and gut homeostasis of Treg cells. The onset of spontaneous colitis in the CD4cre:PP4(f/f) mice further suggests that PP4 is essential for the maintenance of protective gut immunity. The CD4cre:PP4(f/f) mice thus may serve as a good model for studying the interactions between Treg cells and gut commensal bacteria for the regulation of mucosal immunity.

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MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function.

Publications

MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function.

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