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

Jarod A Zepp; Ling Wu; Wen Qian; Wenjun Ouyang; Mark Aronica; Serpil Erzurum; Xiaoxia Li

doi:10.4049/jimmunol.1402647

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

J Immunol. 2015 Mar 15;194(6):2826-37. doi: 10.4049/jimmunol.1402647. Epub 2015 Feb 13.

Authors

Jarod A Zepp¹, Ling Wu², Wen Qian³, Wenjun Ouyang⁴, Mark Aronica⁵, Serpil Erzurum⁵, Xiaoxia Li⁶

Affiliations

¹ 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;
² Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
³ Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195;
⁴ Department of Immunology, Genentech, South San Francisco, CA 94080; and.
⁵ Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.
⁶ 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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Carrier Proteins / genetics
Carrier Proteins / immunology*
Carrier Proteins / metabolism
Cells, Cultured
HEK293 Cells
Humans
Immunoblotting
Inflammation / genetics
Inflammation / immunology*
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 / immunology*
Receptors, Interleukin / metabolism
Receptors, Interleukin-17 / deficiency
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / immunology
Respiratory System / immunology*
Respiratory System / metabolism
Respiratory System / pathology
Signal Transduction / immunology
TNF Receptor-Associated Factor 4 / deficiency
TNF Receptor-Associated Factor 4 / genetics
TNF Receptor-Associated Factor 4 / immunology*
Tyrosine / genetics
Tyrosine / immunology
Tyrosine / metabolism
Ubiquitin-Protein Ligases / deficiency
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / immunology*

Substances

Carrier Proteins
DAZAP2 protein, mouse
Interleukins
Mydgf protein, mouse
RNA-Binding Proteins
Receptors, Interleukin
Receptors, Interleukin-17
TNF Receptor-Associated Factor 4
Traf4 protein, mouse
Tyrosine
Smurf2 protein, mouse
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding