NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development.

EMBO molecular medicine 2021 Mar 05

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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. © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

Citation

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. 2021 Mar 05;13(3):e12834