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

  • EMBO Mol Med. 2021 Mar 5;13(3):e12834. doi: 10.15252/emmm.202012834.
Hsiang-I Tsai  1 ,  Xiaobin Zeng  2  3 ,  Longshan Liu  4 ,  Shengchang Xin  5 ,  Yingyi Wu  1 ,  Zhanxue Xu  1 ,  Huanxi Zhang  4 ,  Gan Liu  1 ,  Zirong Bi  4 ,  Dandan Su  1 ,  Min Yang  1 ,  Yijing Tao  1 ,  Changxi Wang  4 ,  Jing Zhao  5 ,  John E Eriksson  6  7 ,  Wenbin Deng  1 ,  Fang Cheng  1 ,  Hongbo Chen  1
Affiliations
  • 1. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen, China.
  • 2. Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, China.
  • 3. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Medicine School of Shenzhen University, Shenzhen, China.
  • 4. Organ Transplant Centerm, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 5. State Key Laboratory of Coordination Chemistry, Institute of Chemistry and Biomedical Sciences, School of Life Sciences, Nanjing University, Nanjing, China.
  • 6. Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
  • 7. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
PMID: 33555115 DOI: 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.

Keywords
CX5461; NF45/NF90; NFAT; nucleolus; organ transplantation.
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