Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling

Medientyp: E-Artikel
Titel: Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling
Beteiligte: Koch, Lydia [Verfasser:in]; Kespohl, Birte [Verfasser:in]; Agthe, Maria [Verfasser:in]; Schumertl, Tim [Verfasser:in]; Düsterhöft, Stefan [Verfasser:in]; Lemberg, Marius [Verfasser:in]; Lokau, Juliane [Verfasser:in]; Garbers, Christoph [Verfasser:in]
Erschienen: 10 February 2021
Erschienen in: Federation of American Societies for Experimental Biology: The FASEB journal ; 35(2021), 3, Artikel-ID e21380, Seite 1-15
Sprache: Englisch
DOI: 10.25673/96526; 10.1096/fj.202002087R
Identifikator:

Schlagwörter: cytokine ; interleukin-11 ; protease ; RHBDL2 ; rhomboid
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Beschreibung: 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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