Cbx4 Regulates RNA Binding Protein MEX-3B To Thymic stromal lymphopoietin Expression Sumoylation In Epithelium Of HDM-induced Allergic Inflammation

Abstract

Background: Sumoylation is one of the most important posttranslation motificaion implicatied in many biological processes and diseases.However,the role of SUMOylation in allergic airway inflammation has never been reported.

Methods: SUMOylation proteins were detected in epithelium of HDM-induced asthma;Epithelial-derived cytokines(IL-25,IL-33 and TSLP) and hyper-reactivity were assessd in HDM-induced asthma group and SUMOylation inhibitor-treated group.HBE were transfected with SUMOylation E3 ligase CBX4 siRNA to explore the expression of TSLP mRNA and protein.HBE was treated with cycloheximide to explore whether CBX4 regulates TSLP protein stability.Polysome fractionation was performed to analysis TSLP translation after knockdown CBX4 in HBE.Next, to investigate whether CBX4 regulated TSLP translation through RNA binding proteins,we conducted a transcriptome sequenceing analysis.

Results: SUMOylation was enhanced in epithelium of asthma group and inhibition of SUMOylation attenuated airway inflammation.Further,TSLP but not IL-25 and IL-33 induction was suppressed in 2-D08-treated mice.Among several SUMOylation E3 ligases,it was CBX4 involved in regulating TSLP expression in HBE.Mechanistically,CBX4 regulated TSLP translation rather than posttranslational motification. Transcriptome sequenceing analysis show CBX4 promoted TSLP translation through RNA binding protein MEX-3B and MEX-3B binded to the TSLP mRNA and facilictated its translation.

Conclusion: CBX4/MEX-3B/TSLP axis involved in TSLP-mediated airway inflammation,suggesting that targeting SUMO E3 ligase activity of CBX4 would be a novel target for the treatment of asthma.