School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen, China.
Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, China.
EMBO Mol Med. 2021 Mar 5;13(3):e12834. doi: 10.15252/emmm.202012834. Epub 2021 Feb 8.
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.
在此，我们证明了 NFAT，一种免疫反应的关键调节剂，通过在体外 T 细胞激活时触发 NF45/NF90 与 rDNA 启动子中 ARRE2 样序列的直接结合，从细胞质易位到核仁，并与 NF45/NF90 复合物相互作用，共同促进 rDNA 转录。在小鼠心脏或皮肤移植模型以及肾移植患者中也观察到 T 细胞中 pre-rRNA 水平升高。重要的是，通过抑制 NF45/NF90 依赖性 rDNA 转录，可以显著抑制 T 细胞的激活。令人惊讶的是，CX5461，一种 rDNA 转录特异性抑制剂，在效力和脱靶活性（即毒性）方面均优于最常用的免疫抑制剂 FK506，这一系列皮肤和心脏同种异体移植模型得到了证明。总的来说，这揭示了 NF45/NF90 介导的 rDNA 转录是 T 细胞激活所必需的新型信号通路，并为开发安全有效的免疫抑制剂提供了新的靶点。
