TRAF4-SMURF2–Mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation
JA Zepp, L Wu, W Qian, W Ouyang… - The Journal of …, 2015 - journals.aai.org
JA Zepp, L Wu, W Qian, W Ouyang, M Aronica, S Erzurum, X Li
The Journal of Immunology, 2015•journals.aai.orgIL-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 …
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 …
Abstract
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.
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