title: PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation.
abstract: Previous reports have suggested that human CD4(+) CD25(hi)FOXP3(+) T regulatory cells (Tregs) have functional plasticity and may differentiate into effector T cells under inflammation. The molecular mechanisms underlying these findings remain unclear. Here we identified the residue serine 422 of human FOXP3 as a phosphorylation site that regulates its function, which is not present in murine Foxp3. PIM1 kinase, which is highly expressed in human Tregs, was found to be able to interact with and to phosphorylate human FOXP3 at serine 422. T cell receptor (TCR) signaling inhibits PIM1 induction, whereas IL-6 promotes PIM1 expression in in vitro expanded human Tregs. PIM1 negatively regulates FOXP3 chromatin binding activity by specifically phosphorylating FOXP3 at Ser(422). Our data also suggest that phosphorylation of FOXP3 at the Ser(418) site could prevent FOXP3 phosphorylation at Ser(422) mediated by PIM1. Knockdown of PIM1 in in vitro expanded human Tregs promoted FOXP3-induced target gene expression, including CD25, CTLA4, and glucocorticoid-induced tumor necrosis factor receptor (GITR), or weakened FOXP3-suppressed IL-2 gene expression and enhanced the immunosuppressive activity of Tregs. Furthermore, PIM1-specific inhibitor boosted FOXP3 DNA binding activity in in vitro expanded primary Tregs and also enhanced their suppressive activity toward the proliferation of T effector cells. Taken together, our findings suggest that PIM1 could be a new potential therapeutic target in the prevention and treatment of human-specific autoimmune diseases because of its ability to modulate the immunosuppressive activity of human Tregs.
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China,; Department of Surgical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou 350014, China.
authors.forename: Changhua
authors.initials: C
authors.lastname: Zhuo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104.
authors.forename: Guoping
authors.initials: G
authors.lastname: Deng
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zuojia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yin
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Miranda
authors.initials: M
authors.lastname: Piccioni
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Andy
authors.initials: A
authors.lastname: Tsun
authors.affiliation: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Sanjun
authors.initials: S
authors.lastname: Cai
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Philadelphia, Pennsylvania 17013 and.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.affiliation: Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: sh_zhangyu@hotmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China,. Electronic address: binli@sibs.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D010766:Phosphorylation / Q000502:physiology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; C508594:IL2 protein, human; C508017:IL2RA protein, human; C508600:IL6 protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; C491405:TNFRSF18 protein, human; D012694:Serine; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Autoimmune Disease; DNA Binding Protein; FOXP3; Gene Regulation; Immunosuppression; Inflammation; PIM1; Phosphorylation; Tregs
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