Blockade of CBX4-mediated β-catenin SUMOylation attenuates airway epithelial barrier dysfunction in asthma

Epithelial barrier dysfunction is involved in the pathogenesis of asthma. Previous studies show that SUMOylation can regulate epithelial junction molecule localization. However, the role of SUMOylation in epithelial barrier dysfunction in asthma remains unclear. This study found that inhibition of SUMOylation attenuates house dust mite (HDM)-induced epithelial barrier dysfunction. The SUMOylation levels of junction molecules were deter-mined by co-immunoprecipitation (CO-IP) and proximity ligation assay (PLA). HDM treatment significantly enhanced SUMOylation levels of beta-catenin, while no effect was seen on ZO-1, Occludin, and E-cadherin SUMOylation levels. Inhibition of beta-catenin SUMOylation through 2-D08 treatment or SUMOylation modification site mutant (K233A) promoted its membrane localization and repressed Wnt/beta-catenin signaling. Further, we identified that CBX4, an E3 ligase, mediated SUMOylation of beta-catenin. Knockdown of CBX4 promoted beta-catenin membrane localization and improved epithelial barrier function. In vivo analysis showed that AAV6-shCBX4-mediated knockdown of CBX4 attenuated HDM-induced allergic airway inflammation and epithelial barrier dysfunction. The findings showed that inhibiting beta-catenin SUMOylation by targeting CBX4 mitigated HDM-induced epithelial barrier dysfunction in asthma.

Automated summary

This study found that inhibiting SUMOylation can attenuate house dust mite-induced epithelial barrier dysfunction in asthma. The researchers identified CBX4 as the mediator of beta-catenin SUMOylation and showed that silencing CBX4 promotes beta-catenin membrane localization and improves epithelial barrier function.