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

Hypoxic postconditioning (HPC) was reported to stabilize nuclear β-catenin by inhibiting lysine (K)-specific demethylase 2A (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 SCF^KDM2A complex targets nuclear β-catenin for degradation via the ubiquitin-proteasome pathway in vitro. HPC reduced SCF^KDM2A complex and the K48-Ub of β-catenin and increased ubiquitin-specific peptidase 22 (USP22) in the nucleus after tGCI. Furthermore, KDM2A knockdown decreased the K48-Ub of nuclear β-catenin and nuclear β-catenin-SCF^KDM2A 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 by suppressing SCF^KDM2A and increasing USP22, thereby inducing cerebral ischemic tolerance.