CREBBP stabilizes GNG3 protein through acetylation, thereby activating the NF-κB pathway and exacerbating airway inflammation in allergic rhinitis.

Objective: Allergic rhinitis (AR), an allergen-driven chronic inflammatory disorder of nasal mucosa, is characterized by airway inflammation as its cardinal pathological manifestation. While acetylation is known to regulate airway inflammation, its mechanistic involvement in AR-related inflammation remains elusive. This study aims to investigate the acetylation-dependent mechanisms governing airway inflammation in AR.

Materials and methods: RNA-seq analysis identified differentially expressed genes in peripheral blood of AR patients and healthy controls. Ovalbumin-sensitized BALB/c mice were performed as the AR mouse model. Airway inflammation was assessed by measuring inflammatory cytokine levels, inflammatory cell numbers, macrophage counts in whole lung lavage fluid (WLLF), and specific IgE levels in plasma using ELISA and Diff-Quick staining. The underlying mechanism was investigated through Western blotting, immunoprecipitation (IP), and Co-IP.

Results: GNG3 expression was significantly increased in AR patients and the AR mouse model. Knockdown of GNG3 significantly reduced airway inflammation and inhibited NF-κB pathway activation in the AR mouse model. CREBBP overexpression enhanced GNG3 protein stability, and CREBBP mRNA expression was significantly increased in patients with AR and positively correlated with GNG3 expression. Furthermore, GNG3 overexpression restored airway inflammation that was suppressed by CREBBP knockdown in the AR mouse model.

Conclusion: These results demonstrate that CREBBP aggravated airway inflammation in AR by activating the NF-κB pathway via GNG3 upregulation mediated by GNG3 acetylation.