A1 Refereed original research article in a scientific journal
NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development
Authors: Tsai Hsiang-Tsai, Zeng Xiaobin, Liu Longshan, Xin Shenchang, Wu Yingyi, Xu Zhanxue, Zhang Huanxi, Liu Gan, Bi Zirong, Su Dandan, Yang Ming, Tao Yijing, Wang Chanxi, Zhao Jing, Eriksson John E, Deng Wenbin, Cheng Fang, Chen Hongbo
Publisher: WILEY
Publication year: 2021
Journal: EMBO Molecular Medicine
Journal name in source: EMBO MOLECULAR MEDICINE
Journal acronym: EMBO MOL MED
Article number: ARTN e12834
Volume: 13
Issue: 3
Number of pages: 18
ISSN: 1757-4676
eISSN: 1757-4684
DOI: https://doi.org/10.15252/emmm.202012834
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/53632309
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.
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