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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 C, 2022. "Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33733-8
    DOI: 10.1038/s41467-022-33733-8
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    References listed on IDEAS

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    4. Yongyao Fu & Jocelyn Wang & Gayathri Panangipalli & Benjamin J. Ulrich & Byunghee Koh & Chengxian Xu & Rakshin Kharwadkar & Xiaona Chu & Yue Wang & Hongyu Gao & Wenting Wu & Jie Sun & Robert S. Tepper, 2020. "STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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