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

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 consensus sequences in rDNA promoter upon T cell activation in vitro. The elevated pre-rRNA level of T cells are 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.Keyword: NF45/NF90; immunosuppressive agents; organ transplant rejection; calcineurin-NFAT pathway; nucleolus RNA Pol I to rDNA promoter regions. We found that the NF45/NF90-regulation of rRNA transcription positively regulates T cell activation. Suppressing rDNA transcription using the Pol I inhibitor CX5461 significantly inhibited IL-2 secretion, reduced the proliferation of T lymphocytes, and enhanced the survival of mouse skin and heart allografts. This mechanism constitutes a novel therapeutic strategy for immunosuppression.