Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro

Abstract The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts...

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Autores principales:	Charlotte M. Flynn, Yvonne Garbers, Stefan Düsterhöft, Rielana Wichert, Juliane Lokau, Christian H. K. Lehmann, Diana Dudziak, Bernd Schröder, Christoph Becker-Pauly, Stefan Rose-John, Samadhi Aparicio-Siegmund, Christoph Garbers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5fcbad4a86ec408db5a8eceac4164627
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spelling	oai:doaj.org-article:5fcbad4a86ec408db5a8eceac41646272021-12-02T15:11:49ZCathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro10.1038/s41598-020-77884-42045-2322https://doaj.org/article/5fcbad4a86ec408db5a8eceac41646272020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-77884-4https://doaj.org/toc/2045-2322Abstract The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss −/− mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.Charlotte M. FlynnYvonne GarbersStefan DüsterhöftRielana WichertJuliane LokauChristian H. K. LehmannDiana DudziakBernd SchröderChristoph Becker-PaulyStefan Rose-JohnSamadhi Aparicio-SiegmundChristoph GarbersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Charlotte M. Flynn Yvonne Garbers Stefan Düsterhöft Rielana Wichert Juliane Lokau Christian H. K. Lehmann Diana Dudziak Bernd Schröder Christoph Becker-Pauly Stefan Rose-John Samadhi Aparicio-Siegmund Christoph Garbers Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro
description	Abstract The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss −/− mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.
format	article
author	Charlotte M. Flynn Yvonne Garbers Stefan Düsterhöft Rielana Wichert Juliane Lokau Christian H. K. Lehmann Diana Dudziak Bernd Schröder Christoph Becker-Pauly Stefan Rose-John Samadhi Aparicio-Siegmund Christoph Garbers
author_facet	Charlotte M. Flynn Yvonne Garbers Stefan Düsterhöft Rielana Wichert Juliane Lokau Christian H. K. Lehmann Diana Dudziak Bernd Schröder Christoph Becker-Pauly Stefan Rose-John Samadhi Aparicio-Siegmund Christoph Garbers
author_sort	Charlotte M. Flynn
title	Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro
title_short	Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro
title_full	Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro
title_fullStr	Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro
title_full_unstemmed	Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro
title_sort	cathepsin s provokes interleukin-6 (il-6) trans-signaling through cleavage of the il-6 receptor in vitro
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/5fcbad4a86ec408db5a8eceac4164627
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Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro

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