Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 477, Issue 2, Pages 330-338Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2008.06.009
Keywords
apoptosis; CD95; signaling; STAT3; caspase; degradation
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Funding
- Deutsche Forschungsgemeinschaft [GR 3108/1-1]
- Sonderforschungsbereich (SFB)
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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 18 kDa 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. (C) 2008 Elsevier Inc. All rights reserved.
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