title: The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases.
abstract: The pleiotropic activities of Interleukin (IL-)6 are controlled by membrane-bound and soluble forms of the IL-6 receptor (IL-6R) in processes called classic and trans-signaling, respectively. The coding single nucleotide polymorphism (SNP) rs2228145 of the Interleukin 6 receptor (IL-6R Asp358Ala variant) is associated with a 2-fold increase in soluble IL-6R (sIL-6R) serum levels resulting in reduced IL-6-induced C-reactive protein (CRP) production and a reduced risk for coronary heart disease. It was suggested that the increased sIL-6R level leads to decreased IL-6 classic or increased IL-6 trans-signaling. Irrespective of the functional outcome of increased sIL-6R serum level, it is still under debate, whether the increased sIL-6R serum levels emerged from differential splicing or ectodomain shedding. Here we show that increased proteolytic ectodomain shedding mediated by the A Disintegrin and metalloproteinase domain (ADAM) proteases ADAM10 and ADAM17 caused increased sIL-6R serum level in vitro as well as in healthy volunteers homozygous for the IL-6R Asp358Ala allele. Differential splicing of the IL-6R appears to have only a minor effect on sIL-6R level. Increased ectodomain shedding resulted in reduced cell-surface expression of the IL-6R Asp358Ala variant compared to the common IL-6R variant. In conclusion, increased IL-6R ectodomain shedding is a mechanistic explanation for the increased serum IL-6R levels found in persons homozygous for the rs2228145 IL-6R Asp358Ala variant.
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Institute of Biochemistry, Christian-Albrechts-University, Olshausenstraße 40, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Monhasery
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Samadhi
authors.initials: S
authors.lastname: Aparicio-Siegmund
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstraße 40, Kiel, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Lokau
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Baran
authors.affiliation: Institute of Infection and Immunity, The School of Medicine, Cardiff University, Cardiff, CF14 4XN Wales, United Kingdom.
authors.forename: Mari A
authors.initials: MA
authors.lastname: Nowell
authors.affiliation: Institute of Infection and Immunity, The School of Medicine, Cardiff University, Cardiff, CF14 4XN Wales, United Kingdom.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstraße 40, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: jscheller@uni-duesseldorf.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019947:Receptors, Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6; D008565:Membrane Proteins; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: ADAM17; IL-6 trans-signaling; IL-6R; Limited proteolysis; SNP