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<p>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 <i>STUB1</i> gene via activation of the ERK signaling, whereas high levels of ROS compromised STUB1 expression by dampening STUB1 protein half-life. Ablation of <i>Stub1</i> 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.</p>

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STUB1-induced polyubiquitination of SIK3 in alveolar type 2 epithelial cells alleviates severity and outcomes of acute lung injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Feng Tian,
  • Nianlin Xie,
  • Daixing Zhong,
  • Yunfeng Ni,
  • Binghua Zhang,
  • Xiaohua Liang,
  • Jun Ma,
  • Xiaokang Gong,
  • Zhuochen Sun,
  • Jie Zhao,
  • Tao Jiang,
  • Wei Li

摘要

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.