Abstract
Disruption in alveolar type 2 epithelial cells (AT2s) homeostasis by oxidative stress plays an essential role in the pathogenesis of acute lung injury (ALI). However, significant discrepancies remain in understanding the mechanisms for AT2 as a main target for reactive oxygen species (ROS). Herein, we show that STUB1, an E3 ligase involved in protein homeostasis, was dominantly expressed in AT2s. Mild levels of ROS potentiated Nrf2-mediated transactivation of the STUB1 gene via activation of the ERK signaling, whereas high levels of ROS compromised STUB1 expression by dampening STUB1 protein half-life. Ablation of Stub1 in AT2s caused failure in conferring K63-mediated nonproteolytic polyubiquitination of SIK3 (salt-inducible kinase 3), which in turn abrogated CRTC2 (CREB-regulated transcription co-activator 2) substrate binding for SIK3 and thereby triggered CREB signaling-mediated proinflammatory phenotypes. Consequently, disruption in STUB1/SIK3 signaling aggravated lung edema, augmented inflammatory infiltrate, and increased AT2 apoptosis in vivo. Mice lacking STUB1 also demonstrated increased susceptibility to ischemia-reperfusion and overventilation-induced lung injury. These findings unambiguously uncover STUB1 as a critical post-translational regulator of ALI severity and outcomes.
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Acknowledgements
We appreciated Miss Yao Geng (Department of Human Anatomy, Histology and Embryology, Basic Medical Science Academy, Air Force Medical University) for her critical reading of this manuscript.
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This work was supported by the National Natural Science Foundation of China (81770068 to FT, and 31971070 to WL), Key R&D Programs of Shaanxi Province (2022SF-241 to WL) and Science and Technology Development Fund of Air Force Medical University (2022XB002 to WL).
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All protocols involved in animal work were approved by the Institutional Animal Care and Use Committee (IACUC) of Air Force Medical University (Approval #: KY20173012).
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Tian, F., Xie, N., Zhong, D. et al. STUB1-induced polyubiquitination of SIK3 in alveolar type 2 epithelial cells alleviates severity and outcomes of acute lung injury. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08822-x
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DOI: https://doi.org/10.1038/s41419-026-08822-x
