TRAF4-SMURF2介导的DAZAP2降解对IL-25信号传导和过敏性气道炎症至关重要。
TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation.
作者信息
Zepp Jarod A, Wu Ling, Qian Wen, Ouyang Wenjun, Aronica Mark, Erzurum Serpil, Li Xiaoxia
机构信息
Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195;
Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
出版信息
J Immunol. 2015 Mar 15;194(6):2826-37. doi: 10.4049/jimmunol.1402647. Epub 2015 Feb 13.
IL-25 promotes type 2 immunity by inducing the expression of Th2-associated cytokines. Although it is known that the IL-25R (IL-17RB) recruits the adaptor protein ACT1, the IL-25R signaling mechanism remains poorly understood. While screening for IL-25R components, we found that IL-25 responses were impaired in Traf4 (-/-) cells. Administering IL-25 to Traf4 (-/-) mice resulted in blunted airway eosinophilia and Th2 cytokine production. Notably, IL-25R recruitment of TRAF4 was required for the ACT1/IL-25R interaction. Mechanistically, TRAF4 recruited the E3-ligase SMURF2, to degrade the IL-25R-inhibitory molecule DAZAP2. Silencing Dazap2 increased ACT1/IL-25R interaction and IL-25 responsiveness. Moreover, a tyrosine within the IL-25R elicited DAZAP2 interference. This study indicates that TRAF4-SMURF2-mediated DAZAP2 degradation is a crucial initiating event for the IL-25 response.
白细胞介素-25（IL-25）通过诱导Th2相关细胞因子的表达来促进2型免疫。尽管已知IL-25受体（IL-17RB）招募接头蛋白ACT1，但IL-25的信号传导机制仍知之甚少。在筛选IL-25受体成分时，我们发现Traf4基因敲除（-/-）细胞中IL-25反应受损。给Traf4基因敲除（-/-）小鼠注射IL-25会导致气道嗜酸性粒细胞增多和Th2细胞因子产生减弱。值得注意的是，ACT1与IL-25受体的相互作用需要IL-25受体招募TRAF4。从机制上讲，TRAF4招募E3连接酶SMURF2，以降解IL-25受体抑制分子DAZAP2。沉默Dazap2可增加ACT1与IL-25受体的相互作用以及IL-25反应性。此外，IL-25受体中的一个酪氨酸引发了DAZAP2干扰。这项研究表明，TRAF4-SMURF2介导的DAZAP2降解是IL-25反应的关键起始事件。
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