Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signaling and airway inflammation.

RATIONALE: Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of IFN-stimulated genes (ISGs). How asthma genetic susceptible genes modulate cellular response upon viral infection through fine-tuning ISGs induction and subsequent airway inflammation in genetically susceptible asthmatics remains largely unknown.

OBJECTIVES: To decipher the functions of GSDMB in respiratory virus-induced lung inflammation.

METHODS: In two independent cohorts, we analyzed expression correlation between GSDMB and ISGs . In human bronchial epithelial cell line or primary cells, we generated GSDMB-overexpressing and -deficient cells. A series of qPCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISGs induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and applied respiratory syncytial virus (RSV) infection to determine the role of GSDMB on RSV-induced lung inflammation in vivo .

MEASUREMENTS AND MAIN RESULTS: Gasdermin B encoded by GSDMB, one of the most significant asthma-susceptible genes at 17q21, acts as a novel RNA sensor, promoting MAVS-TBK1 signaling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB gene in mouse airway epithelium leads to enhanced ISGs induction, increased airway inflammation with mucus hyper-secretion upon RSV infection.

CONCLUSIONS: GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.