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

Sang-A Park, Yun-Ji Lim, Wai Lim Ku, Dunfang Zhang, Kairong Cui, Liu-Ya Tang, Cheryl Chia, Peter Zanvit, Zuojia Chen, Wenwen Jin, Dandan Wang, Junji Xu, Ousheng Liu, Fu Wang, Alexander Cain, Nancy Guo, Hiroko Nakatsukasa, Chuan Wu, Ying E. Zhang, Keji Zhao () and WanJun Chen ()
Additional contact information
Sang-A Park: National Institutes of Health
Yun-Ji Lim: National Institutes of Health
Wai Lim Ku: National Institutes of Health
Dunfang Zhang: National Institutes of Health
Kairong Cui: National Institutes of Health
Liu-Ya Tang: National Institutes of Health
Cheryl Chia: National Institutes of Health
Peter Zanvit: National Institutes of Health
Zuojia Chen: National Institutes of Health
Wenwen Jin: National Institutes of Health
Dandan Wang: National Institutes of Health
Junji Xu: National Institutes of Health
Ousheng Liu: National Institutes of Health
Fu Wang: National Institutes of Health
Alexander Cain: National Institutes of Health
Nancy Guo: National Institutes of Health
Hiroko Nakatsukasa: National Institutes of Health
Chuan Wu: National Institutes of Health
Ying E. Zhang: National Institutes of Health
Keji Zhao: National Institutes of Health
WanJun Chen: National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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-Ser213) 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-Ser213. 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.

Date: 2022
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DOI: 10.1038/s41467-022-33733-8

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