ADAM17 regulates IL-1 signaling by selectively releasing IL-1 receptor type 2 from the cell surface

• Published in: Cytokine (Philadelphia, Pa.) Vol. 71; no. 2; pp. 238 - 245
• Main Authors: Uchikawa, Shinichi, Yoda, Masaki, Tohmonda, Takahide, Kanaji, Arihiko, Matsumoto, Morio, Toyama, Yoshiaki, Horiuchi, Keisuke
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2015
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAM17 Protein; ADAM17/TACE; Amino Acid Sequence; Animals; Binding Sites - genetics; Blotting, Western; Cells, Cultured; Cercopithecus aethiops; COS Cells; Ectodomain shedding; Embryo, Mammalian - cytology; Fibroblasts - cytology; Fibroblasts - metabolism; IL-1 receptors; Interleukin-1 - metabolism; Mice, Knockout; Molecular Sequence Data; Proteolysis - drug effects; Receptors, Interleukin-1 Type I - genetics; Receptors, Interleukin-1 Type I - metabolism; Receptors, Interleukin-1 Type II - genetics; Receptors, Interleukin-1 Type II - metabolism; Sequence Homology, Amino Acid; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology; JM; PMA; mEFs; IL-1 receptors; ADAM17/TACE; AP; Ectodomain shedding
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2014.10.032

•ADAM17 is the major sheddase for IL-1R2.•The highly conserved JM domain of IL-1R2 is crucial for shedding efficiency.•ADAM17 potentially regulates IL-1 signaling via cleavage of IL-1R2. Interleukin (IL)-1 is one of the most evolutionarily conserved cytokines and plays an essential role in the regulation of innate immunity. IL-1 binds to two different receptors, IL-1R1 and IL-1R2, which share approximately 28% amino acid homology. IL-1R1 contains a cytoplasmic domain and is capable of transducing cellular signals; by contrast, IL-1R2 lacks a functional cytoplasmic domain and serves as a decoy receptor for IL-1. Interestingly, IL-1R2 is proteolytically cleaved and also functions as a soluble receptor that blocks IL-1 activity. In the present study, we examined the shedding properties of IL-1R2 and demonstrate that ADAM17 is de facto the major sheddase for IL-1R2 and that introducing a mutation into the juxta-membrane domain of IL-1R2 significantly desensitizes IL-1R2 to proteolytic cleavage. IL-1R1 was almost insensitive to ADAM17-dependent cleavage; however, the replacement of the juxta-membrane domain of IL-R1 with that of IL-1R2 significantly increased the sensitivity of IL-1R1 to shedding. Furthermore, we demonstrate that ADAM17 indirectly enhances IL-1 signaling in a cell-autonomous manner by selectively cleaving IL-1R2. Taken together, the data collected in the present study indicate that ADAM17 affects sensitivity to IL-1 by changing the balance between IL-1R1 and the decoy receptor IL-1R2.