期刊
JOURNAL OF IMMUNOLOGY
卷 194, 期 6, 页码 2826-2837出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1402647
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资金
- National Institutes of Health/National Institute of Neurological Disorders and Stroke Grant [R01-NS071996]
- National Institutes of Health/National Heart, Lung, and Blood Institute Grant [P01-HL103453]
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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