title: Human and Murine Interleukin 23 Receptors Are Novel Substrates for A Disintegrin and Metalloproteases ADAM10 and ADAM17.
abstract: IL-23 (interleukin 23) regulates immune responses against pathogens and plays a major role in the differentiation and maintenance of TH17 cells and the development of autoimmune diseases and cancer. The IL-23 receptor (IL-23R) complex consists of the unique IL-23R and the common IL-12 receptor β1 (IL-12Rβ1). Differential splicing generates antagonistic soluble IL-23R (sIL-23R) variants, which might limit IL-23-mediated immune responses. Here, ectodomain shedding of human and murine IL-23R was identified as an alternative pathway for the generation of sIL-23R. Importantly, proteolytically released sIL-23R has IL-23 binding activity. Shedding of IL-23R was induced by stimulation with the phorbol ester phorbol 12-myristate 13-acetate (PMA), but not by ionomycin. PMA-induced shedding was abrogated by an ADAM (A disintegrin and metalloprotease) 10 and 17 selective inhibitor, but not by an ADAM10 selective inhibitor. ADAM17-deficient but not ADAM10-deficient HEK293 cells failed to shed IL-23R after PMA stimulation, demonstrating that ADAM17 but not ADAM10 cleaves the IL-23R. Constitutive shedding was, however, inhibited by an ADAM10 selective inhibitor. Using deletions and specific amino acid residue exchanges, we identified critical determinants of ectodomain shedding within the stalk region of the IL-23R. Finally, interaction studies identified domains 1 and 3 of the IL-23R as the main ADAM17 binding sites. In summary, we describe human and murine IL-23R as novel targets for protein ectodomain shedding by ADAM10 and ADAM17.
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany and.
authors.forename: Manuel
authors.initials: M
authors.lastname: Franke
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany and.
authors.forename: Jutta
authors.initials: J
authors.lastname: Schröder
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany and.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Monhasery
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany and.
authors.forename: Theresa
authors.initials: T
authors.lastname: Ackfeld
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany and.
authors.forename: Thorben M
authors.initials: TM
authors.lastname: Hummel
authors.affiliation: the Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: the Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
authors.affiliation: the Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany and.
authors.forename: Doreen M
authors.initials: DM
authors.lastname: Floss
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany and jscheller@uni-duesseldorf.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism*; D000072198:ADAM17 Protein / Q000378:metabolism*; D017398:Alternative Splicing; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D055252:Cell-Derived Microparticles / Q000378:metabolism; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D053759:Interleukin-23 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C515500:IL23R protein, human; D053759:Interleukin-23; D008565:Membrane Proteins; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; D013755:Tetradecanoylphorbol Acetate
keywords: ADAM; ADAM1; ADAM10; IL-23; IL-23R; interleukin; membrane; protease; shedding