Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell Function
Regulatory T cells (Treg cells) are essential for maintaining immune tolerance, and the dysfunction of Treg cells may cause autoimmune diseases and tumors. Forkhead box P3 (FOXP3) is the key transcription factor controlling Treg cell development and suppressive function. Mouse double minute 2 homolo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01087/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Aiting Wang Aiting Wang Mengdi Yang Rui Liang Fangming Zhu Fangming Zhu Fangming Zhu Fuxiang Zhu Fuxiang Zhu Xinnan Liu Yichao Han Ruirong Lin Xiaoxia Wang Dan Li Hecheng Li Xiaojun Yuan Hui Zhao Bin Li |
| spellingShingle |
Aiting Wang Aiting Wang Mengdi Yang Rui Liang Fangming Zhu Fangming Zhu Fangming Zhu Fuxiang Zhu Fuxiang Zhu Xinnan Liu Yichao Han Ruirong Lin Xiaoxia Wang Dan Li Hecheng Li Xiaojun Yuan Hui Zhao Bin Li Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell Function Frontiers in Immunology E3 ubiquitin ligase forkhead box P3 (FOXP3) immunosuppression mouse double minute 2 homolog (MDM2) regulatory T cell (Treg cell) ubiquitination |
| author_facet |
Aiting Wang Aiting Wang Mengdi Yang Rui Liang Fangming Zhu Fangming Zhu Fangming Zhu Fuxiang Zhu Fuxiang Zhu Xinnan Liu Yichao Han Ruirong Lin Xiaoxia Wang Dan Li Hecheng Li Xiaojun Yuan Hui Zhao Bin Li |
| author_sort |
Aiting Wang |
| title |
Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell Function |
| title_short |
Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell Function |
| title_full |
Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell Function |
| title_fullStr |
Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell Function |
| title_full_unstemmed |
Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell Function |
| title_sort |
mouse double minute 2 homolog-mediated ubiquitination facilitates forkhead box p3 stability and positively modulates human regulatory t cell function |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2020-06-01 |
| description |
Regulatory T cells (Treg cells) are essential for maintaining immune tolerance, and the dysfunction of Treg cells may cause autoimmune diseases and tumors. Forkhead box P3 (FOXP3) is the key transcription factor controlling Treg cell development and suppressive function. Mouse double minute 2 homolog (MDM2), an E3 ubiquitin ligase, has been identified as an oncoprotein that mediates the ubiquitination and degradation of tumor suppressor p53; however, whether it has functions in Treg cells remains unknown. Here, we demonstrate that MDM2 positively regulates human Treg cell suppressive function via its mediated ubiquitination and stabilization of FOXP3. Knockdown of MDM2 with shRNA in human primary Treg cells leads to the impaired ability of FOXP3 to regulate the expression levels of downstream genes and the attenuated suppressive capacity of Treg cells, due to FOXP3 instability. Consistently, MDM2 overexpression in human Treg cells enhances FOXP3 stability and Treg cell suppressive capacity. Mechanistically, MDM2 interacts with FOXP3, and mainly mediates monoubiquitination and polyubiquitination of FOXP3, thus stabilizing the protein level of FOXP3. We have also found lysine residues in FOXP3 required for MDM2-mediated ubiquitination. In addition, TCR/CD28 signaling upregulates the expression level of MDM2 and its mediated FOXP3 ubiquitination in human Treg cells. Therefore, our findings reveal that MDM2 in Treg cells could be a potential therapeutic target for treating autoimmune diseases and tumors. |
| topic |
E3 ubiquitin ligase forkhead box P3 (FOXP3) immunosuppression mouse double minute 2 homolog (MDM2) regulatory T cell (Treg cell) ubiquitination |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.01087/full |
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doaj-6c7baed319ee4a789a50f36bd1a926d22020-11-25T02:52:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-06-011110.3389/fimmu.2020.01087538345Mouse Double Minute 2 Homolog-Mediated Ubiquitination Facilitates Forkhead Box P3 Stability and Positively Modulates Human Regulatory T Cell FunctionAiting Wang0Aiting Wang1Mengdi Yang2Rui Liang3Fangming Zhu4Fangming Zhu5Fangming Zhu6Fuxiang Zhu7Fuxiang Zhu8Xinnan Liu9Yichao Han10Ruirong Lin11Xiaoxia Wang12Dan Li13Hecheng Li14Xiaojun Yuan15Hui Zhao16Bin Li17Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaUnit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, ChinaDepartment of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, ChinaDepartment of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaUnit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, ChinaShanghai Key Laboratory of Bio-Energy Crops, School of Life Science, Shanghai University, Shanghai, ChinaDepartment of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaUnit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, ChinaDepartment of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Key Laboratory of Bio-Energy Crops, School of Life Science, Shanghai University, Shanghai, ChinaDepartment of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, ChinaDepartment of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaRegulatory T cells (Treg cells) are essential for maintaining immune tolerance, and the dysfunction of Treg cells may cause autoimmune diseases and tumors. Forkhead box P3 (FOXP3) is the key transcription factor controlling Treg cell development and suppressive function. Mouse double minute 2 homolog (MDM2), an E3 ubiquitin ligase, has been identified as an oncoprotein that mediates the ubiquitination and degradation of tumor suppressor p53; however, whether it has functions in Treg cells remains unknown. Here, we demonstrate that MDM2 positively regulates human Treg cell suppressive function via its mediated ubiquitination and stabilization of FOXP3. Knockdown of MDM2 with shRNA in human primary Treg cells leads to the impaired ability of FOXP3 to regulate the expression levels of downstream genes and the attenuated suppressive capacity of Treg cells, due to FOXP3 instability. Consistently, MDM2 overexpression in human Treg cells enhances FOXP3 stability and Treg cell suppressive capacity. Mechanistically, MDM2 interacts with FOXP3, and mainly mediates monoubiquitination and polyubiquitination of FOXP3, thus stabilizing the protein level of FOXP3. We have also found lysine residues in FOXP3 required for MDM2-mediated ubiquitination. In addition, TCR/CD28 signaling upregulates the expression level of MDM2 and its mediated FOXP3 ubiquitination in human Treg cells. Therefore, our findings reveal that MDM2 in Treg cells could be a potential therapeutic target for treating autoimmune diseases and tumors.https://www.frontiersin.org/article/10.3389/fimmu.2020.01087/fullE3 ubiquitin ligaseforkhead box P3 (FOXP3)immunosuppressionmouse double minute 2 homolog (MDM2)regulatory T cell (Treg cell)ubiquitination |