Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling
Interleukin-11 (IL-11) is a pleiotropic cytokine with both pro- and anti-inflammatory properties. It activates its target cells via binding to the membrane-bound IL-11 receptor (IL-11R), which then recruits a homodimer of the ubiquitously expressed, signal-transducing receptor gp130. Besides this cl...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
10 February 2021
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| In: |
The FASEB journal
Year: 2021, Volume: 35, Issue: 3, Pages: 1-15 |
| ISSN: | 1530-6860 |
| DOI: | 10.25673/96526 |
| Online Access: | Resolving-System, kostenfrei: https://opendata.uni-halle.de//handle/1981185920/98483 Resolving-System, kostenfrei: http://dx.doi.org/10.25673/96526 Resolving-System, kostenfrei: https://doi.org/https://doi.org/10.1096/fj.202002087R Verlag, lizenzpflichtig, Volltext: https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.202002087R 
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| Author Notes: | Lydia Koch, Birte Kespohl, Maria Agthe, Tim Schumertl, Stefan Düsterhöft, Marius K. Lemberg, Juliane Lokau, Christoph Garbers |
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| 245 | 1 | 0 | |a Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling |c Lydia Koch, Birte Kespohl, Maria Agthe, Tim Schumertl, Stefan Düsterhöft, Marius K. Lemberg, Juliane Lokau, Christoph Garbers |
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| 520 | |a Interleukin-11 (IL-11) is a pleiotropic cytokine with both pro- and anti-inflammatory properties. It activates its target cells via binding to the membrane-bound IL-11 receptor (IL-11R), which then recruits a homodimer of the ubiquitously expressed, signal-transducing receptor gp130. Besides this classic signaling pathway, IL-11 can also bind to soluble forms of the IL-11R (sIL-11R), and IL-11/sIL-11R complexes activate cells via the induction of gp130 homodimerization (trans-signaling). We have previously reported that the metalloprotease ADAM10 cleaves the membrane-bound IL-11R and thereby generates sIL-11R. In this study, we identify the rhomboid intramembrane protease RHBDL2 as a so far unrecognized alternative sheddase that can efficiently trigger IL-11R secretion. We determine the cleavage site used by RHBDL2, which is located in the extracellular part of the receptor in close proximity to the plasma membrane, between Ala-370 and Ser-371. Furthermore, we identify critical amino acid residues within the transmembrane helix that are required for IL-11R proteolysis. We also show that ectopically expressed RHBDL2 is able to cleave the IL-11R within the early secretory pathway and not only at the plasma membrane, indicating that its subcellular localization plays a central role in controlling its activity. Moreover, RHBDL2-derived sIL-11R is biologically active and able to perform IL-11 trans-signaling. Finally, we show that the human mutation IL-11R-A370V does not impede IL-11 classic signaling, but prevents RHBDL2-mediated IL-11R cleavage. | ||
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| 650 | 4 | |a cytokine | |
| 650 | 4 | |a interleukin-11 | |
| 650 | 4 | |a protease | |
| 650 | 4 | |a RHBDL2 | |
| 650 | 4 | |a rhomboid | |
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