CBX4 Regulates Long-Form Thymic Stromal Lymphopoietin-mediated Airway Inflammation through SUMOylation in House Dust Mite-induced Asthma

Thymic stromal lymphopoietin presents in two distinct isoforms: short-form (sfTSLP) and long-form (lfTSLP). lfTSLP promotes inflammation, whereas sfTSLP inhibits inflammation, in allergic asthma. However, little is known about the regulation of lfTSLP and sfTSLP during allergic attack in the asthma airway epithelium. Here, we report that small ubiquitin-like modifier (SUMOylation) was enhanced in house dust mite-induced allergic asthma airway epithelium. Inhibition of SUMOylation significantly alleviated airway T-helper cell type 2 inflammation and lfTSLP expression. Mechanistically, chromobox 4 (CBX4), a SUMOylation E3 ligase, enhanced lfTSLP mRNA translation, but not sfTSLP, through the RNA-binding protein muscle excess (MEX)-3B. MEX-3B promoted lfTSLP translation by binding the lfTSLP mRNA through its K homology domains. Furthermore, CBX4 regulated MEX-3B transcription in human bronchial epithelial cells through enhancing SUMOylation concentrations of the transcription factor TFII-I. In conclusion, we demonstrate an important mechanism whereby CBX4 promotes MEX-3B transcription through enhancing TFII-I SUMOylation and MEX-3B enhances the expression of lfTSLP through binding to the lfTSLP mRNA and promoting its translation. Our findings uncover a novel target of CBX4 for therapeutic agents for lfTSLP-mediated asthma.

Automated summary

This study reveals that small ubiquitin-like modifier (SUMOylation) is enhanced in the airway epithelium of house dust mite-induced allergic asthma. Inhibition of SUMOylation alleviates airway inflammation and lfTSLP expression. Mechanistically, SUMOylation enhances the transcription of MEX-3B through the transcription factor TFII-I, and MEX-3B promotes lfTSLP translation by binding to its mRNA. This finding highlights CBX4 as a potential therapeutic target for lfTSLP-mediated asthma.