NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development
Open Access
- 8 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 13 (3), e12834
- https://doi.org/10.15252/emmm.202012834
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.Funding Information
- Sun Yat-sen University (20ykzd17 and 20ykpy122)
- Natural Science Foundation of Guangdong Province (2020A1515011465, 2020A151501467)
- China Postdoctoral Science Foundation (2018M643299)
- National Natural Science Foundation of China-Shandong Joint Fund for Marine Science Research Centers (81700655, 81702750, 82001698, 81970145, 81670141)
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