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 homodimer of ubiquitously expressed, signal-transducing gp130. Besides this classic signaling pathway, can also bind soluble forms IL-11R (sIL-11R), IL-11/sIL-11R complexes activate induction gp130 homodimerization (trans-signaling). We have previously reported that metalloprotease ADAM10 cleaves thereby generates sIL-11R. In study, we identify rhomboid intramembrane protease RHBDL2 as so far unrecognized alternative sheddase efficiently trigger secretion. determine cleavage site used by RHBDL2, located in extracellular part close proximity plasma membrane, between Ala-370 Ser-371. Furthermore, critical amino acid residues within transmembrane helix are required for proteolysis. show ectopically expressed able cleave early secretory pathway not only at indicating subcellular localization plays central role controlling activity. Moreover, RHBDL2-derived sIL-11R biologically active perform trans-signaling. Finally, human mutation IL-11R-A370V does impede signaling, but prevents RHBDL2-mediated cleavage.