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.
journal_name
PLoS Bioljournal_title
PLoS biologyauthors
Riethmueller S,Somasundaram P,Ehlers JC,Hung CW,Flynn CM,Lokau J,Agthe M,Düsterhöft S,Zhu Y,Grötzinger J,Lorenzen I,Koudelka T,Yamamoto K,Pickhinke U,Wichert R,Becker-Pauly C,Rädisch M,Albrecht A,Hessefort M,Stahnkedoi
10.1371/journal.pbio.2000080subject
Has Abstractpub_date
2017-01-06 00:00:00pages
e2000080issue
1eissn
1544-9173issn
1545-7885pii
pbio.2000080journal_volume
15pub_type
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