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Interleukin‐11 (IL‐11) receptor cleavage by the rhomboid protease RHBDL2 induces IL‐11 trans‐signaling
Author(s) -
Koch Lydia,
Kespohl Birte,
Agthe Maria,
Schumertl Tim,
Düsterhöft Stefan,
Lemberg Marius K.,
Lokau Juliane,
Garbers Christoph
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002087r
Subject(s) - rhomboid , microbiology and biotechnology , glycoprotein 130 , signal transduction , receptor , biology , transmembrane protein , extracellular , proteases , chemistry , biochemistry , enzyme , stat3
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.