The role of NEDD4-mediated ubiquitination of AQP5 in allergic rhinitis: implications for nasal mucosal barrier function.

BACKGROUND

Allergic rhinitis (AR) pathology is mainly due to disruption of the nasal epithelial barrier, but the role of aquaporin 5 (AQP5) is not fully understood. We propose that the E3 ubiquitin ligase NEDD4 is responsible for the degradation of AQP5 and thus affects barrier homeostasis in AR.

METHODS

Human nasal epithelial cells and ovalbumin-induced Sprague-Dawley rats were used as in vitro and in vivo models, respectively. Control and AR groups were compared with siNEDD4 and ovAQP5 groups using co-immunoprecipitation, confocal microscopy, and ubiquitination assays to assess molecular interactions. Transepithelial electrical resistance (TER), MUC5AC secretion, and cytokine release were used to measure barrier function.

RESULTS

We demonstrated that NEDD4 directly interacts with and ubiquitinates AQP5 at lysine 257, leading to its proteasomal degradation. NEDD4 was upregulated by IL-13, and this upregulation did not alter AQP5 mRNA levels. Decreasing NEDD4 or increasing AQP5 expression restored barrier integrity and inhibited MUC5AC and IL-6/IL-8 synthesis and concomitantly suppressed p38 MAPK activation; this suppression is consistent with AQP5-mediated signaling. Inhibiting p38 with SB203580 restored barrier function and counteracted mucus hypersecretion. Nasal administration of siNEDD4 or ovAQP5 in rats relieved allergic reactions, reduced inflammatory cell infiltration, and normalized NEDD4/p-p38/AQP5 expression.

CONCLUSIONS

We have identified the NEDD4-AQP5 axis as a crucial driver of AR and a potential therapeutic target.