Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784809666587394048 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9568563 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT parksanga opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT limyunji opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT kuwailim opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT zhangdunfang opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT cuikairong opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT tangliuya opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT chiacheryl opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT zanvitpeter opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT chenzuojia opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT jinwenwen opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT wangdandan opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT xujunji opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT liuousheng opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT wangfu opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT cainalexander opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT guonancy opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT nakatsukasahiroko opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT wuchuan opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT zhangyinge opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT zhaokeji opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation AT chenwanjun opposingfunctionsofcircadianproteindbpandatypicale2ffamilye2f8inantitumorth9celldifferentiation |