1 Department of Medicine, Baylor College of Medicine, Houston, Texas; and.
Am J Respir Crit Care Med. 2014 Jan 1;189(1):16-29. doi: 10.1164/rccm.201305-0874OC.
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.
To evaluate the role of STUB1 (STIP1 homology and U-Box containing protein 1) in regulating IL-4R signaling in airway inflammation.
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.
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.
Our study identified a previously uncharacterized role for STUB1 in regulating IL-4R signaling, which might provide a new strategy for attenuating airway inflammation.
IL-4Rα 是 IL-4 和 IL-13 的共同受体成分，在调节气道炎症和重塑的 IL-4 和 IL-13 介导的信号通路中发挥关键作用。然而，IL-4Rα 周转及其信号终止的调节机制仍不清楚。
评估 STUB1（STIP1 同源和 U-Box 含有蛋白 1）在调节气道炎症中 IL-4R 信号的作用。
通过免疫印迹、免疫沉淀和流式细胞术研究 STUB1 在 IL-4Rα 降解及其信号中的作用。通过测量 STUB1（-/-）小鼠肺炎症细胞浸润、粘液产生、血清 lgE 水平和肺泡巨噬细胞 M2 激活，在体内确定 STUB1 参与气道炎症的情况。评估哮喘患者气道上皮和慢性阻塞性肺疾病患者肺组织中的 STUB1 表达。
STUB1 与 IL-4Rα 相互作用，并将其靶向泛素化介导的蛋白酶体降解，从而终止 IL-4 或 IL-13 信号。STUB1 敲除细胞显示 IL-4Rα 水平升高且 STAT6 持续激活，而 STUB1 过表达则降低 IL-4Rα 水平。缺乏 STUB1 的小鼠自发发生气道炎症、肺泡巨噬细胞的替代 M2 激活和血清 IgE 增加。在哮喘或慢性阻塞性肺疾病患者的气道中，STUB1 水平升高，提示 STUB1 的上调可能是气道炎症中抑制 IL-4R 信号的重要反馈机制。
我们的研究确定了 STUB1 在调节 IL-4R 信号中的一个以前未被描述的作用，这可能为减轻气道炎症提供一种新策略。
