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 upon T cell activationin 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..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 01. Okt. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tsai, Hsiang-i [VerfasserIn] |
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| doi: |
10.1101/2020.05.26.116897 |
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| PPN (Katalog-ID): |
XBI018039901 |
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| 245 | 1 | 0 | |a NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development |
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| 520 | |a 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 activationin 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. | ||
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| 700 | 1 | |a Zeng, Xiaobin |0 (orcid)0000-0002-3111-9202 |4 aut | |
| 700 | 1 | |a Liu, Longshan |4 aut | |
| 700 | 1 | |a Xin, Shengchang |4 aut | |
| 700 | 1 | |a Wu, Yingyi |4 aut | |
| 700 | 1 | |a Xu, Zhanxue |4 aut | |
| 700 | 1 | |a Zhang, Huanxi |4 aut | |
| 700 | 1 | |a Liu, Gan |4 aut | |
| 700 | 1 | |a Bi, Zirong |4 aut | |
| 700 | 1 | |a Su, Dandan |4 aut | |
| 700 | 1 | |a Yang, Min |4 aut | |
| 700 | 1 | |a Tao, Yijing |4 aut | |
| 700 | 1 | |a Wang, Changxi |4 aut | |
| 700 | 1 | |a Zhao, Jing |4 aut | |
| 700 | 1 | |a Eriksson, John E. |4 aut | |
| 700 | 1 | |a Deng, Wenbin |4 aut | |
| 700 | 1 | |a Cheng, Fang |4 aut | |
| 700 | 1 | |a Chen, Hongbo |0 (orcid)0000-0002-0954-5600 |4 aut | |
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