TRAF4-SMURF2–Mediated DAZAP2 Degradation Is Critical for IL-25 Signaling and Allergic Airway Inflammation
Year: 2015
Type: article
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.
Source: The Journal of Immunology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Asthma Inflammation Research, G1842643373, Molecular and Cellular Mechanisms of IL-17 Signaling, Medical Scientist Training Program, Pathobiology of Asthma, Airway redox biochemistry as a deteriminant of asthma phenotype during adolescen*, Pulmonary Hypertension Breakthrough Initiative, Immunology Training Program-Predoctoral
OpenAlex ID: W1498924706