TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation.

Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE

Publication: Bethesda, MD : American Association of Immunologists
Original Publication: Baltimore : Williams & Wilkins, c1950-

Carrier Proteins/*immunology ; Inflammation/*immunology ; Receptors, Interleukin/*immunology ; Respiratory System/*immunology ; TNF Receptor-Associated Factor 4/*immunology ; Ubiquitin-Protein Ligases/*immunology; Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cells, Cultured ; HEK293 Cells ; Humans ; Immunoblotting ; Inflammation/genetics ; Inflammation/metabolism ; Interleukins/immunology ; Interleukins/pharmacology ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Immunological ; Mutation ; Proteolysis ; RNA Interference ; RNA-Binding Proteins ; Receptors, Interleukin/genetics ; Receptors, Interleukin/metabolism ; Receptors, Interleukin-17/deficiency ; Receptors, Interleukin-17/genetics ; Receptors, Interleukin-17/immunology ; Respiratory System/metabolism ; Respiratory System/pathology ; Signal Transduction/immunology ; TNF Receptor-Associated Factor 4/deficiency ; TNF Receptor-Associated Factor 4/genetics ; Tyrosine/genetics ; Tyrosine/immunology ; Tyrosine/metabolism ; Ubiquitin-Protein Ligases/deficiency ; Ubiquitin-Protein Ligases/genetics

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.
(Copyright © 2015 by The American Association of Immunologists, Inc.)

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R01 NS071996 United States NS NINDS NIH HHS; T32 AI089474 United States AI NIAID NIH HHS; P01 HL081064 United States HL NHLBI NIH HHS; U10 HL109250 United States HL NHLBI NIH HHS; R01-NS071996 United States NS NINDS NIH HHS; P01-HL103453 United States HL NHLBI NIH HHS; T32 GM007250 United States GM NIGMS NIH HHS; R24 HL123767 United States HL NHLBI NIH HHS; P01 HL103453 United States HL NHLBI NIH HHS

0 (Carrier Proteins)
0 (DAZAP2 protein, mouse)
0 (Interleukins)
0 (Mydgf protein, mouse)
0 (RNA-Binding Proteins)
0 (Receptors, Interleukin)
0 (Receptors, Interleukin-17)
0 (TNF Receptor-Associated Factor 4)
0 (Traf4 protein, mouse)
42HK56048U (Tyrosine)
EC 2.3.2.26 (Smurf2 protein, mouse)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)

Date Created: 20150215 Date Completed: 20150619 Latest Revision: 20220316

20240829

PMC4366881

10.4049/jimmunol.1402647

25681341