Proteolytic Cleavage Governs Interleukin-11 Trans-signaling

  • Cell Rep. 2016 Feb 23;14(7):1761-1773. doi: 10.1016/j.celrep.2016.01.053.
Juliane Lokau  1 ,  Rebecca Nitz  2 ,  Maria Agthe  1 ,  Niloufar Monhasery  2 ,  Samadhi Aparicio-Siegmund  1 ,  Neele Schumacher  1 ,  Janina Wolf  1 ,  Katja Möller-Hackbarth  1 ,  Georg H Waetzig  3 ,  Joachim Grötzinger  1 ,  Gerhard Müller-Newen  4 ,  Stefan Rose-John  1 ,  Jürgen Scheller  5 ,  Christoph Garbers  6
Affiliations
  • 1. Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
  • 2. Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
  • 3. CONARIS Research Institute AG, 24118 Kiel, Germany.
  • 4. Institute of Biochemistry and Molecular Biology, RWTH Aachen, 52074 Aachen, Germany.
  • 5. Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany. Electronic address: [email protected].
  • 6. Institute of Biochemistry, Kiel University, 24098 Kiel, Germany. Electronic address: [email protected].
PMID: 26876177 DOI: 10.1016/j.celrep.2016.01.053
Abstract

Interleukin (IL)-11 has been shown to be a crucial factor for intestinal tumorigenesis, lung carcinomas, and asthma. IL-11 is thought to exclusively mediate its biological functions through cell-type-specific expression of the membrane-bound IL-11 Receptor (IL-11R). Here, we show that the metalloprotease ADAM10, but not ADAM17, can release the IL-11R ectodomain. Chimeric proteins of the IL-11R and the IL-6 receptor (IL-6R) revealed that a small juxtamembrane portion is responsible for this substrate specificity of ADAM17. Furthermore, we show that the serine proteases neutrophil Elastase and proteinase 3 can also cleave the IL-11R. The resulting soluble IL-11R (sIL-11R) is biologically active and binds IL-11 to activate cells. This IL-11 trans-signaling pathway can be inhibited specifically by the anti-inflammatory therapeutic compound sgp130Fc. In conclusion, proteolysis of the IL-11R represents a molecular switch that controls the IL-11 trans-signaling pathway and widens the number of cells that can be activated by IL-11.

Keywords
ADAM10; ADAM17; interleukin-11; proteolysis; signal transduction.