2. Academic Validation
  3. Proteolytic Cleavage Governs Interleukin-11 Trans-signaling

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

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.

Figures