Proteolytic Cleavage Governs Interleukin-11 Trans-signaling | Zendy

Juliane Lokau | Zendy; Rebecca Nitz | Zendy; Maria Agthe | Zendy; Niloufar Monhasery | Zendy; Samadhi Aparicio-Siegmund | Zendy; Neele Schumacher | Zendy; Janina Wolf | Zendy; Katja MöllerHackbarth | Zendy; Georg H. Waetzig | Zendy; Joachim Grötzinger | Zendy; Gerhard MüllerNewen | Zendy; Stefan RoseJohn | Zendy; Jürgen Scheller | Zendy; Christoph Garbers | Zendy

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Proteolytic Cleavage Governs Interleukin-11 Trans-signaling

Author(s) -

Juliane Lokau,

Rebecca Nitz,

Maria Agthe,

Niloufar Monhasery,

Samadhi Aparicio-Siegmund,

Neele Schumacher,

Janina Wolf,

Katja MöllerHackbarth,

Georg H. Waetzig,

Joachim Grötzinger,

Gerhard MüllerNewen,

Stefan RoseJohn,

Jürgen Scheller,

Christoph Garbers

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.01.053

Subject(s) - ectodomain , proteases , microbiology and biotechnology , proteolysis , signal transduction , metalloproteinase , biology , receptor , adam10 , chemistry , matrix metalloproteinase , disintegrin , biochemistry , enzyme

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.

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