OTUD6A in Airway Epithelial Cells Exacerbates Allergic Asthma by Promoting Airway Inflammation and Airway Remodeling Through Deubiquitination of hResistin/mRELMα

Asthma is a prevalent chronic airway disorder characterized by airway hyperresponsiveness (AHR), persistent airway inflammation, and airway remodeling. Emerging evidence implicates ubiquitination-a critical post-translational modification-in asthma pathogenesis. The study identifies ovarian tumor deubiquitinase 6A (OTUD6A), a deubiquitinase with established oncogenic roles, as a novel regulator of airway inflammation and remodeling. The study finds a significantly upregulation of OTUD6A in asthma patients and murine lungs, with predominant localization in airway epithelial cells. Genetic ablation of Otud6a prevents house dust mite (HDM)-induced AHR, airway inflammation, mucin hypersecretion in both chronic and acute asthma models, as well as airway remodeling in chronic asthma model. Mechanistically, multi-omics analysis identifies the secreted cytokine human (h)Resistin/mouse resistin-like molecule α (mRELMα) as a substrate of OTUD6A. OTUD6A deubiquitinates and stabilizes hResistin by specifically removing its K48-linked polyubiquitin chains at lysines K2 and K19 via the catalytic residue C152, thereby blocking its proteasomal degradation and promoting its secretion. The consequent accumulation of hResistin potentiates epithelial alarms production and facilitates epithelial-mesenchymal transition, driving airway inflammation and airway remodeling. Furthermore, adeno-associated virus 6-mediated OTUD6A silencing in murine lungs markedly ameliorates asthma phenotypes. These findings establish a pathogenic OTUD6A-hResistin/mRELMα axis and nominating OTUD6A as a promising therapeutic target for asthma intervention.