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

Hsiang‐I Tsai,Dandan Su,Yijing Tao,Zhanxue Xu,Zirong Bi,Yingyi Wu,Wenbin Deng,Gan Liu,Changxi Wang,Hongbo Chen,Jing Zhao,Longshan Liu,John E Eriksson,Fang Cheng,Huanxi Zhang,Xiaobin Zeng,Min Yang,Shengchang Xin

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.

Highlights

The inhibition of T cell activation is crucial for both the prevention of organ transplantation rejection and graft-versus-host disease (GVHD) that accompanies allogeneic hematopoietic stem cell transplantation, as well as in the treatment of certain autoimmune diseases (Coghill et al, 2011, Ichiki et al, 2006, Petrelli & Van Wijk, 2016, Szyska & Na, 2016)
NF45/NF90 was previously identified by mass spectrometry to recognize the upstream ARRE2 consensus sequence of the IL-2 promoter in activated T cells, and NF45/NF90 is speculated to mediate T cell activation by regulating IL-2 transcription (Shi et al, 2007a)
We postulate that the main contribution of NF45/NF90 to T cell activation occurs through the regulation of rDNA transcription, as opposed to IL-2 transcription, for the following reasons

Summary

Introduction

The inhibition of T cell activation is crucial for both the prevention of organ transplantation rejection and graft-versus-host disease (GVHD) that accompanies allogeneic hematopoietic stem cell transplantation, as well as in the treatment of certain autoimmune diseases (Coghill et al, 2011, Ichiki et al, 2006, Petrelli & Van Wijk, 2016, Szyska & Na, 2016). The calcineurin–NFAT (nuclear factor of activated T cells) binding inhibitors cyclosporine A (CsA) and tacrolimus (FK506) have proven highly effective at suppressing T cell response to allografts, and are among the most widely used immunosuppressive drugs to significantly prolong graft survival and reduce patient morbidity (Monostory, 2018). The use of these immunosuppressive agents has been reported in a variety of autoimmune diseases (Kovarik & Burtin, 2003). The discovery of novel mechanisms of early T cell activation that obviate the inhibition of calcineurin is of great value in the search for safer and more efficient immunosuppressive agents

Methods

Results

Conclusion