NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development
Abstract Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2‐like sequences in rDNA promoter...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012834 |
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| author | Hsiang‐i Tsai Xiaobin Zeng Longshan Liu Shengchang Xin Yingyi Wu Zhanxue Xu Huanxi Zhang Gan Liu Zirong Bi Dandan Su Min Yang Yijing Tao Changxi Wang Jing Zhao John E Eriksson Wenbin Deng Fang Cheng Hongbo Chen |
| author_facet | Hsiang‐i Tsai Xiaobin Zeng Longshan Liu Shengchang Xin Yingyi Wu Zhanxue Xu Huanxi Zhang Gan Liu Zirong Bi Dandan Su Min Yang Yijing Tao Changxi Wang Jing Zhao John E Eriksson Wenbin Deng Fang Cheng Hongbo Chen |
| author_sort | Hsiang‐i Tsai |
| collection | DOAJ |
| description | Abstract Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2‐like sequences in rDNA promoter upon T‐cell activation in vitro. The elevated pre‐rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T‐cell activation can be significantly suppressed by inhibiting NF45/NF90‐dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription‐specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off‐target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90‐mediated rDNA transcription as a novel signaling pathway essential for T‐cell activation and as a new target for the development of safe and effective immunosuppressants. |
| format | Article |
| id | doaj-art-a63fdeff89ba40b9b30a6caeff5ad0b3 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a63fdeff89ba40b9b30a6caeff5ad0b32025-08-20T04:03:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-02-0113311810.15252/emmm.202012834NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant developmentHsiang‐i Tsai0Xiaobin Zeng1Longshan Liu2Shengchang Xin3Yingyi Wu4Zhanxue Xu5Huanxi Zhang6Gan Liu7Zirong Bi8Dandan Su9Min Yang10Yijing Tao11Changxi Wang12Jing Zhao13John E Eriksson14Wenbin Deng15Fang Cheng16Hongbo Chen17School of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversityCenter Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan UniversityOrgan Transplant Centerm, The First Affiliated Hospital, Sun Yat‐sen UniversityState Key Laboratory of Coordination Chemistry, Institute of Chemistry and Biomedical Sciences, School of Life Sciences, Nanjing UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversityOrgan Transplant Centerm, The First Affiliated Hospital, Sun Yat‐sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversityOrgan Transplant Centerm, The First Affiliated Hospital, Sun Yat‐sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversityOrgan Transplant Centerm, The First Affiliated Hospital, Sun Yat‐sen UniversityState Key Laboratory of Coordination Chemistry, Institute of Chemistry and Biomedical Sciences, School of Life Sciences, Nanjing UniversityCell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat‐Sen UniversityAbstract Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2‐like sequences in rDNA promoter upon T‐cell activation in vitro. The elevated pre‐rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T‐cell activation can be significantly suppressed by inhibiting NF45/NF90‐dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription‐specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off‐target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90‐mediated rDNA transcription as a novel signaling pathway essential for T‐cell activation and as a new target for the development of safe and effective immunosuppressants.https://doi.org/10.15252/emmm.202012834CX5461NF45/NF90NFATnucleolusorgan transplantation |
| spellingShingle | Hsiang‐i Tsai Xiaobin Zeng Longshan Liu Shengchang Xin Yingyi Wu Zhanxue Xu Huanxi Zhang Gan Liu Zirong Bi Dandan Su Min Yang Yijing Tao Changxi Wang Jing Zhao John E Eriksson Wenbin Deng Fang Cheng Hongbo Chen NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development EMBO Molecular Medicine CX5461 NF45/NF90 NFAT nucleolus organ transplantation |
| title | NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development |
| title_full | NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development |
| title_fullStr | NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development |
| title_full_unstemmed | NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development |
| title_short | NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development |
| title_sort | nf45 nf90 mediated rdna transcription provides a novel target for immunosuppressant development |
| topic | CX5461 NF45/NF90 NFAT nucleolus organ transplantation |
| url | https://doi.org/10.15252/emmm.202012834 |
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