title: Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling.
abstract: Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction.
authors.affiliation: Institute of Anatomy, University of Kiel, 24118 Kiel, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Arnold
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Boll
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rothaug
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Neele
authors.initials: N
authors.lastname: Schumacher
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Rielana
authors.initials: R
authors.lastname: Wichert
authors.affiliation: Institute of Anatomy, University of Kiel, 24118 Kiel, Germany.
authors.forename: Janna
authors.initials: J
authors.lastname: Schneppenheim
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Lokau
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Pickhinke
authors.affiliation: Systematic Proteomics &Bioanalytics; Institute of Experimental Medicine; University of Kiel, 24105 Kiel, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Koudelka
authors.affiliation: Systematic Proteomics &Bioanalytics; Institute of Experimental Medicine; University of Kiel, 24105 Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tholey
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Institute of Anatomy, University of Kiel, 24118 Kiel, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Lucius
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
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; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility
chemical_list: C508603:IL6R protein, human; D008565:Membrane Proteins; D019947:Receptors, Interleukin-6; D053829:Amyloid Precursor Protein Secretases; D008666:Metalloendopeptidases; C053833:meprin A; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human