IRAK2 Ubiquitination Mediated by PELI1 Impairs Airway Epithelial Function and Accelerates Pediatric Asthma.

PELI1, an E3 ubiquitin ligase, has been identified as a controller of the innate immune response. This study was designed to expound the functional role of PELI1 in asthma (AS). Newborn mice were induced with house dust mite (HDM) to establish a mouse model of AS, and overexpression of Peli1 was performed specifically in airway epithelial cells by AAV6.2 vector. Human bronchial epithelial cell line 16HBE was induced with HDM, PELI1 was overexpressed in 16HBE cells by liposome transfection, and knockout was elicited through CRISPR/Cas9. Peli1 expression was reduced in the airway epithelium of newborn mice induced with HDM, and overexpression of Peli1 alleviated airway inflammation, mitigated airway injury, and inhibited airway remodeling in AS mice. PELI1 induced protein degradation of IRAK2 through K63 ubiquitination modification. Ectopic expression of Irak2 abated the mitigating effect of Peli1 overexpression on airway inflammation by activating the Mapk/Nfκb signaling. Blockade of the MAPK/NF-κB signaling mitigated the exacerbation of inflammatory responses and cellular damage in 16HBE cells induced by IRAK2 overexpression. Taken together, this research reveals a functional role of PELI1 in IRAK2 degradation and airway inflammation, which provides novel insights into the treatment of pediatric AS.