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<p>Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with limited clinical therapeutic effects to suspend its progression. Circular RNAs (circRNAs) possess regulatory effects in various diseases. However, circRNA-involved regulatory mechanisms in COPD are largely unknown. This study reveals the mechanism of SMURF1-mediated BECN1 ubiquitination, which is competed by Ub-K48 and Ub-K63, driving the circPDE4D-regulated autophagy. Here, circPDE4D is first identified as a downregulated circRNA in COPD. Among patients with COPD, the lower expression of circPDE4D is associated with the reduced lung function values of FEV<sub>1</sub>/FVC%, FEV<sub>1</sub>%, and MMEF<sub>75/25</sub>% predicted. Moreover, circPDE4D promotes autophagy and SG formation, as well as relieves inflammation in vitro and in vivo. Mechanistically, circPDE4D binds with miR545-3p to regulate SMURF1, which functions in apoptosis, autophagy, SG formation, and inflammation. Importantly, SMURF1 interacts with BECN1 to form a complex and recruits Ub-K63 to enhance K63-linked ubiquitination of BECN1, whereas it antagonizes Ub-K48 to govern BECN1 stability. In particular, circPDE4D is indispensable for the SMURF1-induced BECN1 ubiquitination and can enhance the stability of BECN1. Together, this circPDE4D-miR545-3p-SMURF1-BECN1 regulatory feedback loop underlies the circPDE4D-mediated functions and provides valuable insights into the therapeutic application potential of COPD drugs and biomarkers developed based on circPDE4D.</p><p></p>

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K48 and K63 linkage-competed ubiquitination of BECN1 promotes circPDE4D-mediated autophagy in chronic obstructive pulmonary disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Ting-Ting Chen,
  • Ming-Yu Wang,
  • Jia-Ying Kang,
  • Guo-Chun Ou,
  • Ru Wang,
  • Da-Wei Zhang,
  • Jing-Jing Ye,
  • Guang-He Fei

摘要

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with limited clinical therapeutic effects to suspend its progression. Circular RNAs (circRNAs) possess regulatory effects in various diseases. However, circRNA-involved regulatory mechanisms in COPD are largely unknown. This study reveals the mechanism of SMURF1-mediated BECN1 ubiquitination, which is competed by Ub-K48 and Ub-K63, driving the circPDE4D-regulated autophagy. Here, circPDE4D is first identified as a downregulated circRNA in COPD. Among patients with COPD, the lower expression of circPDE4D is associated with the reduced lung function values of FEV1/FVC%, FEV1%, and MMEF75/25% predicted. Moreover, circPDE4D promotes autophagy and SG formation, as well as relieves inflammation in vitro and in vivo. Mechanistically, circPDE4D binds with miR545-3p to regulate SMURF1, which functions in apoptosis, autophagy, SG formation, and inflammation. Importantly, SMURF1 interacts with BECN1 to form a complex and recruits Ub-K63 to enhance K63-linked ubiquitination of BECN1, whereas it antagonizes Ub-K48 to govern BECN1 stability. In particular, circPDE4D is indispensable for the SMURF1-induced BECN1 ubiquitination and can enhance the stability of BECN1. Together, this circPDE4D-miR545-3p-SMURF1-BECN1 regulatory feedback loop underlies the circPDE4D-mediated functions and provides valuable insights into the therapeutic application potential of COPD drugs and biomarkers developed based on circPDE4D.