title: TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation.
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.
authors: 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;
authors: Jarod A
authors: JA
authors: Zepp
authors: Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
authors: Ling
authors: L
authors: Wu
authors: Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195;
authors: Wen
authors: W
authors: Qian
authors: Department of Immunology, Genentech, South San Francisco, CA 94080; and.
authors: Wenjun
authors: W
authors: Ouyang
authors: Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.
authors: Mark
authors: M
authors: Aronica
authors: Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.
authors: Serpil
authors: S
authors: Erzurum
authors: 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; lix@ccf.org.
authors: Xiaoxia
authors: X
authors: Li
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D009154:Mutation; D059748:Proteolysis; D034622:RNA Interference; D016601:RNA-Binding Proteins; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012137:Respiratory System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D053449:TNF Receptor-Associated Factor 4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014443:Tyrosine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; C000598698:DAZAP2 protein, mouse; D007378:Interleukins; C442281:Mydgf protein, mouse; D016601:RNA-Binding Proteins; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D053449:TNF Receptor-Associated Factor 4; C506368:Traf4 protein, mouse; D014443:Tyrosine; C533325:Smurf2 protein, mouse; D044767:Ubiquitin-Protein Ligases