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

doi:10.15252/emmm.202012834

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

^*Korresponderande författare för detta arbete

Biokemi och cellbiologi

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

9 Citeringar (Scopus)

172 Nedladdningar (Pure)

Sammanfattning

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.

Originalspråk	Engelska
Artikelnummer	e12834
Tidskrift	EMBO Molecular Medicine
Volym	13
Nummer	3
DOI	https://doi.org/10.15252/emmm.202012834
Status	Publicerad - 5 mars 2021
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

Finansiering

This research was supported by the National Natural Science Foundation of China (81702750, 81670141, 81970145, 81700655 and 82001698); Natural Science Foundation of Guangdong Province (2020A1515011465 and 2020A151501467); Science, Technology & Innovation Commission of Shenzhen Municipality (JCYJ20170818164756460, JCYJ20180307154700308, JCYJ20170818163844015, JCYJ20180307151420045, and JCYJ20190807151609464); Sun Yat‐sen University (20ykzd17 and 20ykpy122); International Collaboration of Science and Technology of Guangdong Province (2020A0505100031); China Postdoctoral Science Foundation (2018M643299).

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10.15252/emmm.202012834

EMMM-13-e12834Slutlig publicerad version, 3,77 MBLicens: CC BY

https://urn.fi/URN:NBN:fi-fe2022021519049

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Tsai, H. I., Zeng, X., Liu, L., Xin, S., Wu, Y., Xu, Z., Zhang, H., Liu, G., Bi, Z., Su, D., Yang, M., Tao, Y., Wang, C., Zhao, J., Eriksson, J. E., Deng, W., Cheng, F., & Chen, H. (2021). NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development. EMBO Molecular Medicine, 13(3), Artikel e12834. https://doi.org/10.15252/emmm.202012834

@article{deeb98adba6146cfb4e06bf070e56d32,

title = "NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development",

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",

author = "Tsai, \{Hsiang i.\} and Xiaobin Zeng and Longshan Liu and Shengchang Xin and Yingyi Wu and Zhanxue Xu and Huanxi Zhang and Gan Liu and Zirong Bi and Dandan Su and Min Yang and Yijing Tao and Changxi Wang and Jing Zhao and Eriksson, \{John E.\} and Wenbin Deng and Fang Cheng and Hongbo Chen",

note = "Funding Information: This research was supported by the National Natural Science Foundation of China (81702750, 81670141, 81970145, 81700655 and 82001698); Natural Science Foundation of Guangdong Province (2020A1515011465 and 2020A151501467); Science, Technology \& Innovation Commission of Shenzhen Municipality (JCYJ20170818164756460, JCYJ20180307154700308, JCYJ20170818163844015, JCYJ20180307151420045, and JCYJ20190807151609464); Sun Yat‐sen University (20ykzd17 and 20ykpy122); International Collaboration of Science and Technology of Guangdong Province (2020A0505100031); China Postdoctoral Science Foundation (2018M643299). Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2021",

month = mar,

day = "5",

doi = "10.15252/emmm.202012834",

language = "English",

volume = "13",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

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T1 - NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development

AU - Tsai, Hsiang i.

AU - Zeng, Xiaobin

AU - Liu, Longshan

AU - Xin, Shengchang

AU - Wu, Yingyi

AU - Xu, Zhanxue

AU - Zhang, Huanxi

AU - Liu, Gan

AU - Bi, Zirong

AU - Su, Dandan

AU - Yang, Min

AU - Tao, Yijing

AU - Wang, Changxi

AU - Zhao, Jing

AU - Eriksson, John E.

AU - Deng, Wenbin

AU - Cheng, Fang

AU - Chen, Hongbo

N1 - Funding Information: This research was supported by the National Natural Science Foundation of China (81702750, 81670141, 81970145, 81700655 and 82001698); Natural Science Foundation of Guangdong Province (2020A1515011465 and 2020A151501467); Science, Technology & Innovation Commission of Shenzhen Municipality (JCYJ20170818164756460, JCYJ20180307154700308, JCYJ20170818163844015, JCYJ20180307151420045, and JCYJ20190807151609464); Sun Yat‐sen University (20ykzd17 and 20ykpy122); International Collaboration of Science and Technology of Guangdong Province (2020A0505100031); China Postdoctoral Science Foundation (2018M643299). Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license

PY - 2021/3/5

Y1 - 2021/3/5

N2 - 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.

AB - 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.

KW - CX5461

KW - NF45/NF90

KW - NFAT

KW - nucleolus

KW - organ transplantation

UR - https://www.scopus.com/pages/publications/85100819740

U2 - 10.15252/emmm.202012834

DO - 10.15252/emmm.202012834

M3 - Article

C2 - 33555115

AN - SCOPUS:85100819740

SN - 1757-4676

VL - 13

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 3

M1 - e12834

ER -

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

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