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.

中文翻译：

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NF45 / NF90介导的rDNA转录为免疫抑制剂的发展提供了新的靶标

在本文中，我们证明NFAT是免疫应答的关键调节因子，它从细胞质转移到核仁并与NF45 / NF90复合物相互作用，通过触发NF45 / NF90与rDNA启动子中的ARRE2样序列的直接结合，共同促进rDNA转录。在体外T细胞活化后。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细胞的pre-rRNA水平升高。重要的是，可以通过抑制NF45 / NF90依赖性rDNA转录来显着抑制T细胞活化。令人惊讶的是，就一系列功效而言，无论是效力还是脱靶活性（即毒性），CX5461（一种rDNA转录特异性抑制剂）的性能均优于最常用的免疫抑制剂FK506，这已通过一系列皮肤和心脏异体移植模型得到证实。总的来说，