2. Academic Validation
  3. NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development

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

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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