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<p>The accumulation of HIFs regulated by the PHD-pVHL pathway represents the classical mechanism that transcriptionally mediates cellular adaptation to hypoxia. Extensive hypoxic stress activates cell death. Comprehensive understanding the mechanisms of hypoxia-induced cell death is essential for treatment of several diseases. Here, we revealed that β-TrCP1 degradation is essential for hypoxia-induced cell death and tissue injury. Hypoxia promotes β-TrCP1 degradation via proteasome pathway in HIFs-independent manner, and SMURF2 is identified as the corresponding E3 ligase. Additionally, acetylation of β-TrCP1 decreases after hypoxia, which is required for β-TrCP1 degradation. Tip60 establishes the acetylation of β-TrCP1 under normoxic conditions and is prolyl-hydroxylated by PHD2. Prolyl Hydroxylation stabilizes Tip60 under normoxic conditions, while hypoxia promotes the degradation of Tip60 by decreasing its prolyl hydroxylation. HDAC8 catalyses the deacetylation of β-TrCP1, which is enhanced after hypoxia. Loss of β-TrCP1 acetylation after hypoxia promotes the binding of SMURF2 to β-TrCP1 and its degradation. p53 is a substrate of β-TrCP1, and loss of β-TrCP1 upon hypoxia results in the accumulation of p53, which is responsible for hypoxia-induced cell death and tissue injury. Thus, this study illustrates a previously unappreciated posttranscriptional hypoxia-responsive mechanism constituted by PHD2-Tip60-HDAC8-SMURF2-β-TrCP1 degradation axis to promote p53 accumulation to mediate cell death and tissue injury.</p> Graphical abstract <p></p>

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Tip60-HDAC8-SMURF2-mediated β-TrCP1 degradation is a key mechanism for hypoxia-induced cell death and tissue injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月27日

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  • Sheng Li,
  • Bo-Wen Zhang,
  • Zi-Juan Wei,
  • Yan Xi,
  • Guo-An Zhang,
  • Yue Zhang,
  • De-Chi Kou,
  • Xiao-Peng Song,
  • Jing Huang,
  • Ping Song,
  • Ke-Yi Liang,
  • Shuai-Shuai Pei,
  • Hong-Yu Feng,
  • Si-Ping Li,
  • Qian-Qian Lou,
  • Yue Liu,
  • Kun-Hou Yao,
  • Lu Yang,
  • Su Chen

摘要

The accumulation of HIFs regulated by the PHD-pVHL pathway represents the classical mechanism that transcriptionally mediates cellular adaptation to hypoxia. Extensive hypoxic stress activates cell death. Comprehensive understanding the mechanisms of hypoxia-induced cell death is essential for treatment of several diseases. Here, we revealed that β-TrCP1 degradation is essential for hypoxia-induced cell death and tissue injury. Hypoxia promotes β-TrCP1 degradation via proteasome pathway in HIFs-independent manner, and SMURF2 is identified as the corresponding E3 ligase. Additionally, acetylation of β-TrCP1 decreases after hypoxia, which is required for β-TrCP1 degradation. Tip60 establishes the acetylation of β-TrCP1 under normoxic conditions and is prolyl-hydroxylated by PHD2. Prolyl Hydroxylation stabilizes Tip60 under normoxic conditions, while hypoxia promotes the degradation of Tip60 by decreasing its prolyl hydroxylation. HDAC8 catalyses the deacetylation of β-TrCP1, which is enhanced after hypoxia. Loss of β-TrCP1 acetylation after hypoxia promotes the binding of SMURF2 to β-TrCP1 and its degradation. p53 is a substrate of β-TrCP1, and loss of β-TrCP1 upon hypoxia results in the accumulation of p53, which is responsible for hypoxia-induced cell death and tissue injury. Thus, this study illustrates a previously unappreciated posttranscriptional hypoxia-responsive mechanism constituted by PHD2-Tip60-HDAC8-SMURF2-β-TrCP1 degradation axis to promote p53 accumulation to mediate cell death and tissue injury.

Graphical abstract