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Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation

Interleukin-9 (IL-9)-producing CD4(+) T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-β), is still lacking. Here we show opposing funct...

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Autores principales: Park, Sang-A, Lim, Yun-Ji, Ku, Wai Lim, Zhang, Dunfang, Cui, Kairong, Tang, Liu-Ya, Chia, Cheryl, Zanvit, Peter, Chen, Zuojia, Jin, Wenwen, Wang, Dandan, Xu, Junji, Liu, Ousheng, Wang, Fu, Cain, Alexander, Guo, Nancy, Nakatsukasa, Hiroko, Wu, Chuan, Zhang, Ying E., Zhao, Keji, Chen, WanJun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9568563/
https://www.ncbi.nlm.nih.gov/pubmed/36241625
http://dx.doi.org/10.1038/s41467-022-33733-8
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author Park, Sang-A
Lim, Yun-Ji
Ku, Wai Lim
Zhang, Dunfang
Cui, Kairong
Tang, Liu-Ya
Chia, Cheryl
Zanvit, Peter
Chen, Zuojia
Jin, Wenwen
Wang, Dandan
Xu, Junji
Liu, Ousheng
Wang, Fu
Cain, Alexander
Guo, Nancy
Nakatsukasa, Hiroko
Wu, Chuan
Zhang, Ying E.
Zhao, Keji
Chen, WanJun
author_facet Park, Sang-A
Lim, Yun-Ji
Ku, Wai Lim
Zhang, Dunfang
Cui, Kairong
Tang, Liu-Ya
Chia, Cheryl
Zanvit, Peter
Chen, Zuojia
Jin, Wenwen
Wang, Dandan
Xu, Junji
Liu, Ousheng
Wang, Fu
Cain, Alexander
Guo, Nancy
Nakatsukasa, Hiroko
Wu, Chuan
Zhang, Ying E.
Zhao, Keji
Chen, WanJun
author_sort Park, Sang-A
collection PubMed
description Interleukin-9 (IL-9)-producing CD4(+) T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-β), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-β and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser(213)) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser(213). Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.
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spelling pubmed-95685632022-10-16 Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation Park, Sang-A Lim, Yun-Ji Ku, Wai Lim Zhang, Dunfang Cui, Kairong Tang, Liu-Ya Chia, Cheryl Zanvit, Peter Chen, Zuojia Jin, Wenwen Wang, Dandan Xu, Junji Liu, Ousheng Wang, Fu Cain, Alexander Guo, Nancy Nakatsukasa, Hiroko Wu, Chuan Zhang, Ying E. Zhao, Keji Chen, WanJun Nat Commun Article Interleukin-9 (IL-9)-producing CD4(+) T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-β), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-β and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser(213)) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser(213). Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation. Nature Publishing Group UK 2022-10-14 /pmc/articles/PMC9568563/ /pubmed/36241625 http://dx.doi.org/10.1038/s41467-022-33733-8 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Park, Sang-A
Lim, Yun-Ji
Ku, Wai Lim
Zhang, Dunfang
Cui, Kairong
Tang, Liu-Ya
Chia, Cheryl
Zanvit, Peter
Chen, Zuojia
Jin, Wenwen
Wang, Dandan
Xu, Junji
Liu, Ousheng
Wang, Fu
Cain, Alexander
Guo, Nancy
Nakatsukasa, Hiroko
Wu, Chuan
Zhang, Ying E.
Zhao, Keji
Chen, WanJun
Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
title Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
title_full Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
title_fullStr Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
title_full_unstemmed Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
title_short Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation
title_sort opposing functions of circadian protein dbp and atypical e2f family e2f8 in anti-tumor th9 cell differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9568563/
https://www.ncbi.nlm.nih.gov/pubmed/36241625
http://dx.doi.org/10.1038/s41467-022-33733-8
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