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Abstract
Rationale: IL-4Rα, the common receptor component for IL-4 and IL-13, plays a critical role in IL-4- and IL-13-mediated signaling pathways that regulate airway inflammation and remodeling. However, the regulatory mechanisms underlying IL-4Rα turnover and its signal termination remain elusive.
Objectives: To evaluate the role of STUB1 (STIP1 homology andU-Box containingprotein1) inregulatingIL-4Rsignalinginairwayinflammation.
Methods: The roles of STUB1 in IL-4Rα degradation and its signaling were investigated by immunoblot, immunoprecipitation, and flow cytometry. The involvement of STUB1 in airway inflammation was determined in vivo by measuring lung inflammatory cells infiltration, mucus production, serum lgE levels, and alveolar macrophage M2 activation in STUB1-/- mice. STUB1 expression was evaluated in airway epithelium of patients with asthma and lung tissues of subjects with chronic obstructive pulmonary disease.
Measurements and Main Results: STUB1 interacted with IL-4Rα and targeted it for ubiquitination-mediated proteasomal degradation, terminating IL-4 or IL-13 signaling. STUB1 knockout cells showed increased levels of IL-4Rα and sustained STAT6 activation, whereas STUB1 overexpression reduced IL-4Rα levels. Mice deficient in STUB1 had spontaneous airway inflammation, alternative M2 activation of alveolar macrophage, and increased serum IgE. STUB1 levels were increased in airways of subjects with asthma or chronic obstructive pulmonary disease, suggesting that up-regulation of STUB1 might be an important feedback mechanism to dampen IL-4R signaling in airway inflammation.
Conclusions: Our study identified a previously uncharacterized role for STUB1 in regulating IL-4R signaling, which might provide a new strategy for attenuating airway inflammation.
Keywords: IL-4R signaling; STUB1; airway inflammation
As a key determinant of Th2 immune response and inflammation, IL-4R signaling pathway plays a critical role in the pathogenesis of asthmatic airway inflammation (1, 2) and other diseases including helminth infections (3), rheumatoid arthritis (4), diabetes (5), and cancer (6, 7). IL-4Rα, a common receptor subunit shared by IL-4 and IL-13, is essential for signal transduction by both cytokines. IL-4Rα associates with cytokine receptor common g chain (gc) to form type I IL-4R receptor, a receptor exclusive for IL-4, or pairs with IL-13Ra1 to form type II IL-4 receptor, which is activated by both IL-4 and IL-13 (1). The binding of IL-4 or IL-13 to IL-4 receptors induces activation of Janus kinases, which then initiates several signaling cascades that result in the binding of phosphorylated signal transducer and activator of transcription 6...