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 SCFKDM2A complex targets nuclear β-catenin for degradation
via the ubiquitin-proteasome pathway in vitro. HPC reduced
SCFKDM2A 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-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 by
suppressing SCFKDM2A and increasing USP22, thereby inducing cerebral
ischemic tolerance.