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Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling

Author

Listed:
  • Jinjin Yu

    (Bengbu Medical University
    Universiti Sains Malaysia
    Bengbu Medical University)

  • Yingke Li

    (Xinxiang Medical University)

  • Yiming Li

    (Bengbu Medical University)

  • Xiaotian Liu

    (Bengbu Medical University)

  • Qingyang Huo

    (Xinxiang Medical University)

  • Nan Wu

    (Bengbu Medical University)

  • Yangxia Zhang

    (Xinxiang Medical University)

  • Taoling Zeng

    (Xiamen University)

  • Yong Zhang

    (Bengbu Medical University)

  • Henry You Li

    (University of Canterbury)

  • Jie Lian

    (Xinxiang Medical University)

  • Jihong Zhou

    (Bengbu Medical University)

  • Emmanuel Jairaj Moses

    (Universiti Sains Malaysia)

  • Jian Geng

    (Bengbu Medical University)

  • Juntang Lin

    (Xinxiang Medical University)

  • Wei Li

    (Bengbu Medical University)

  • Xinxing Zhu

    (Bengbu Medical University)

Abstract

The transcriptional repressor FOXN3 plays a key role in regulating pulmonary inflammatory responses, which are crucial in the development of pulmonary fibrosis. However, its specific regulatory function in lung fibrosis remains unclear. Here, we show that FOXN3 suppresses pulmonary fibrosis by inhibiting Smad transcriptional activity. FOXN3 targets a substantial number of Smad response gene promoters, facilitating Smad4 ubiquitination, which disrupts the association of the Smad2/3/4 complex with chromatin and abolishes its transcriptional response. In response to pro-fibrotic stimuli, NEK6 phosphorylates FOXN3 at S412 and S416, leading to its degradation. The loss of FOXN3 inhibits β-TrCP-mediated ubiquitination of Smad4, stabilizing the Smad complex’s association with its responsive elements and promoting transcriptional activation, thus contributing to the development of pulmonary fibrosis. Notably, we found a significant inverse expression pattern between FOXN3 and Smad4 in clinical pulmonary fibrosis cases, underscoring the importance of the NEK6-FOXN3-Smad axis in the pathological process of pulmonary fibrosis.

Suggested Citation

  • Jinjin Yu & Yingke Li & Yiming Li & Xiaotian Liu & Qingyang Huo & Nan Wu & Yangxia Zhang & Taoling Zeng & Yong Zhang & Henry You Li & Jie Lian & Jihong Zhou & Emmanuel Jairaj Moses & Jian Geng & Junta, 2025. "Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56922-7
    DOI: 10.1038/s41467-025-56922-7
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    References listed on IDEAS

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    1. Elena Astanina & Gabriella Doronzo & Davide Corà & Francesco Neri & Salvatore Oliviero & Tullio Genova & Federico Mussano & Emanuele Middonti & Edoardo Vallariello & Chiara Cencioni & Donatella Valdem, 2022. "The TFEB-TGIF1 axis regulates EMT in mouse epicardial cells," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
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