title: Cleavage Site Localization Differentially Controls Interleukin-6 Receptor Proteolysis by ADAM10 and ADAM17.
abstract: Limited proteolysis of the Interleukin-6 Receptor (IL-6R) leads to the release of the IL-6R ectodomain. Binding of the cytokine IL-6 to the soluble IL-6R (sIL-6R) results in an agonistic IL-6/sIL-6R complex, which activates cells via gp130 irrespective of whether the cells express the IL-6R itself. This signaling pathway has been termed trans-signaling and is thought to mainly account for the pro-inflammatory properties of IL-6. A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 are the major proteases that cleave the IL-6R. We have previously shown that deletion of a ten amino acid long stretch within the stalk region including the cleavage site prevents ADAM17-mediated cleavage, whereas the receptor retained its full biological activity. In the present study, we show that deletion of a triple serine (3S) motif (Ser-359 to Ser-361) adjacent to the cleavage site is sufficient to prevent IL-6R cleavage by ADAM17, but not ADAM10. We find that the impaired shedding is caused by the reduced distance between the cleavage site and the plasma membrane. Positioning of the cleavage site in greater distance towards the plasma membrane abrogates ADAM17-mediated shedding and reveals a novel cleavage site of ADAM10. Our findings underline functional differences in IL-6R proteolysis by ADAM10 and ADAM17.
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Riethmueller
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Ehlers
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Lokau
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Düsterhöft
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Knittler
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dombrowsky
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004252:DNA Mutational Analysis; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: D008565:Membrane Proteins; D019947:Receptors, Interleukin-6; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human