NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development. Issue 3 (8th February 2021)

• Record Type: Journal Article
• Authors: Tsai, Hsiang‐i; Zeng, Xiaobin; Liu, Longshan; Xin, Shengchang; Wu, Yingyi; Xu, Zhanxue; Zhang, Huanxi; Liu, Gan; Bi, Zirong; Su, Dandan; Yang, Min; Tao, Yijing; Wang, Changxi; Zhao, Jing; Eriksson, John E; Deng, Wenbin; Cheng, Fang; Chen, Hongbo
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-02-08
• Subjects: CX5461 -- NF45/NF90 -- NFAT -- nucleolus -- organ transplantation; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202012834
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: This study reveals NFAT‐NF45/NF90‐mediated rDNA transcription as a key regulating axis in modulating T cell activation. Targeting ribosome biogenesis could be a novel immunosuppressive therapy for organ transplantation. NF45/NF90 protein complex positively regulates rDNA transcription by directly binding to rDNA gene promoter. Upon T cell activation, NAFT translocates to nucleolus and interacts with NF45/NF90 to cooperatively promote rDNA transcription. Knockdown of NF45/NF90 or inhibiting rDNA transcription using a polymerase I inhibitor CX5461 suppresses T cell activation. CX5461 treatment prolongs the survival of mouse skin or heart allografts even more than the most commonly used suppressant FK506. Abstract : This study reveals NFAT‐NF45/NF90‐mediated rDNA transcription as a key regulating axis in modulating T cell activation. Targeting ribosome biogenesis could be a novel immunosuppressive therapy for organ transplantation.