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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalEMBO Molecular Medicine
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • CX5461
  • NF45/NF90
  • NFAT
  • nucleolus
  • organ transplantation

ASJC Scopus subject areas

  • Molecular Medicine

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