title: Caspase-mediated cleavage of the signal-transducing IL-6 receptor subunit gp130.
abstract: The present study characterizes the molecular mechanisms of CD95L-induced inhibition of IL-6 signaling, which is known to mediate hepatoprotective effects in response to various toxins. CD95L-induced caspase activation leads to degradation of gp130, thereby suppressing IL-6-induced phosphorylation of STAT3 (Tyr(705)) and of tyrosine phosphatase SHP2 (Tyr(580)). Degradation of gp130 protein in response to CD95L was largely prevented after inhibition of caspase 3 or 8. Introduction of a point mutation into a newly identified caspase cleavage site located within position 800-806 (DHVDGGD) of the cytoplasmic tail of gp130 leads to cleavage resistance of the respective receptor in an in vitro assay with recombinant active caspase 3. Correspondingly, the release of a C-terminal gp130-cleavage product of approximately 18kDa was also inhibited after mutagenesis of this cleavage motif. In conclusion, this study demonstrates that caspase activation by CD95L antagonizes IL-6 signaling by a caspase-mediated cleavage of gp130 thereby probably counteracting hepatoprotective effects of IL-6.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. DirkGraf@gmx.net
authors.forename: Dirk
authors.initials: D
authors.lastname: Graf
authors.forename: Katrin
authors.initials: K
authors.lastname: Haselow
authors.forename: Ivo
authors.initials: I
authors.lastname: Münks
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008297:Male; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D021122:Protein Subunits; D050822:Cytokine Receptor gp130; D020169:Caspases