2. Academic Validation
  3. Inhibition of SCFKDM2A/USP22-dependent nuclear β-catenin ubiquitylation mediates cerebral ischemic tolerance

Inhibition of SCFKDM2A/USP22-dependent nuclear β-catenin ubiquitylation mediates cerebral ischemic tolerance

  • Commun Biol. 2025 Feb 11;8(1):214. doi: 10.1038/s42003-025-07644-5.
Yunyan Zuo # 1 2,  Jiahui Xue # 1,  Haixia Wen # 1 3,  Lixuan Zhan 1,  Meiyan Chen 1,  Weiwen Sun 1,  En Xu 4
Affiliations

Affiliations

  • 1 Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 2 Department of Neurology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China.
  • 3 Department of Neurology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
  • 4 Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China. enxu@163.net.
  • # Contributed equally.
PMID: 39934243 DOI: 10.1038/s42003-025-07644-5
Abstract

Hypoxic postconditioning (HPC) was reported to stabilize nuclear β-catenin by inhibiting lysine (K)-specific demethylase 2 A (KDM2A) in hippocampal CA1 against transient global cerebral ischemia (tGCI). Herein we investigate how HPC inhibits the K48-linked poly-ubiquitination (K48-Ub)-related degradation of nuclear β-catenin in CA1 after tGCI. We confirmed that SCFKDM2A complex targets nuclear β-catenin for degradation via ubiquitin Proteasome pathway in vitro. HPC reduced SCFKDM2A complex and the K48-Ub of β-catenin, and increased Ubiquitin-Specific Peptidase 22 (USP22) in nucleus after tGCI. Furthermore, KDM2A knockdown decreased the K48-Ub of nuclear β-catenin and nuclear β-catenin-SCFKDM2A complex interaction after tGCI. Moreover, β-catenin knockdown suppressed nuclear Survivin expression and attenuated neuroprotection induced by HPC. In contrast, the overexpression of USP22 promoted nuclear β-catenin deubiquitination and enhanced the neuroprotective effects offered by HPC. Taken together, this study supports that HPC downregulated the K48-Ub of nuclear β-catenin through suppressing SCFKDM2A and increasing USP22, thereby inducing cerebral ischemic tolerance.

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