Marrack, Philippa, Riethmueller, Steffen, Somasundaram, Prasath, Ehlers, Johanna C., Hung, Chien-Wen, Flynn, Charlotte M., Lokau, Juliane, Agthe, Maria, Düsterhöft, Stefan, Zhu, Yijue, Grötzinger, Joachim, Lorenzen, Inken, Koudelka, Tomas, Yamamoto, Kosuke, Pickhinke, Ute, Wichert, Rielana, Becker-Pauly, Christoph, Rädisch, Marisa, Albrecht, Alexander, Hessefort, Markus, Stahnke, Dominik, Unverzagt, Carlo, Rose-John, Stefan, Tholey, Andreas and Garbers, Christoph (2017) Proteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role of N-Glycosylation. PLOS Biology, 15 (1). e2000080. DOI 10.1371/journal.pbio.2000080.

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Abstract

Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography–mass spectrometry to identify an sIL-6R form in human serum that originates from proteolytic cleavage, map its cleavage site between Pro-355 and Val-356, and determine the occupancy of all O- and N-glycosylation sites of the human sIL-6R. The metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) uses this cleavage site in vitro, and mutation of Val-356 is sufficient to completely abrogate IL-6R proteolysis. N- and O-glycosylation were dispensable for signaling of the IL-6R, but proteolysis was orchestrated by an N- and O-glycosylated sequon near the cleavage site and an N-glycan exosite in domain D1. Proteolysis of an IL-6R completely devoid of glycans is significantly impaired. Thus, glycosylation is an important regulator for sIL-6R generation.

Document Type:	Article
Research affiliation:	Kiel University > Kiel Marine Science OceanRep > The Future Ocean - Cluster of Excellence
Refereed:	Yes
Open Access Journal?:	Yes
Publisher:	Public Library of Science (PLoS)
Projects:	Future Ocean
Date Deposited:	08 Jan 2018 11:16
Last Modified:	11 Jul 2019 15:35
URI:	https://oceanrep.geomar.de/id/eprint/41256

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