title: Mammalian Sterile 20-like Kinase 1 (Mst1) Enhances the Stability of Forkhead Box P3 (Foxp3) and the Function of Regulatory T Cells by Modulating Foxp3 Acetylation.
abstract: Regulatory T cells (Tregs) play crucial roles in maintaining immune tolerance. The transcription factor Foxp3 is a critical regulator of Treg development and function, and its expression is regulated at both transcriptional and post-translational levels. Acetylation by lysine acetyl transferases/lysine deacetylases is one of the main post-translational modifications of Foxp3, which regulate Foxp3's stability and transcriptional activity. However, the mechanism(s) by which the activities of these lysine acetyl transferases/lysine deacetylases are regulated to preserve proper Foxp3 acetylation during Treg development and maintenance of Treg function remains to be determined. Here we report that Mst1 can enhance Foxp3 stability, its transcriptional activity, and Treg function by modulating the Foxp3 protein at the post-translational level. We discovered that Mst1 could increase the acetylation of Foxp3 by inhibiting Sirt1 activity, which requires the Mst1 kinase activity. We also found that Mst1 could attenuate Sirt1-mediated deacetylation of Foxp3 through directly interacting with Foxp3 to prevent or interfere the interaction between Sirt1 and Foxp3. Therefore, Mst1 can regulate Foxp3 stability in kinase-dependent and kinase-independent manners. Finally, we showed that treatment of Mst1(-/-) Tregs with Ex-527, a Sirt1-specific inhibitor, partially restored the suppressive function of Mst1(-/-) Tregs. Our studies reveal a novel mechanism by which Mst1 enhances Foxp3 expression and Treg function at the post-translational level.
authors.affiliation: the Obstetrics and Gynecology Hospital and Institute of Reproduction and Development, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China, and From the Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China, the Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Xingrong
authors.initials: X
authors.lastname: Du
authors.affiliation: From the Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Shi
authors.affiliation: From the Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Kejing
authors.initials: K
authors.lastname: Deng
authors.affiliation: the Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 hongbo.chi@stjude.org.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.affiliation: the Obstetrics and Gynecology Hospital and Institute of Reproduction and Development, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China, and From the Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China, wufan_tao@fudan.edu.cn.
authors.forename: Wufan
authors.initials: W
authors.lastname: Tao
mesh_terms: D000107:Acetylation; D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology; D015533:Transcriptional Activation
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D056564:Sirtuin 1
keywords: Forkhead box P3 (FOXP3); MST1 (mammalian sterile 20-like kinase 1); acetylation; post-translational modification (PTM); regulatory T cell; sirtuin 1 (SIRT1)