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

Year: 2025

Type: article

Abstract: 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. Hypoxia promotes the proteasome-mediated β-TrCP1 degradation via SMURF2. Tip60-HDAC8-regulated β-TrCP1 acetylation affects hypoxia-induced β-TrCP1 degradation. PHD2 prolyl-hydroxylates and stabilizes Tip60 under normoxic conditions, and Tip60 is degraded after hypoxia as losing the prolyl hydroxylation. β-TrCP1 degradation is essential for hypoxia-induced cell death and tissue injury by targeting p53.

Source: Cellular and Molecular Life Sciences

DOI: 10.1007/s00018-025-05983-4