Visit our Expo - Redox and Inflammation signaling 2012

VIII. Inflammation specific signaling Poster VIII, 33
Receptor interacting protein RIP1, a crucial initiator of inflammation and necrotic cell
death
Authors: Tom Vanden Berghe, Miki Kalai, Nele Festjens, Jill Demeulemeester, Kathleen
D’Hondt and Peter Vandenabeele
Molecular Signaling and Cell Death Unit, Department of Molecular Biomedical
Research, VIB, Ghent University, Technologiepark 927, 9052 Zwijnaarde, Belgium
Receptor interacting protein (RIP1) is recruited to tumor necrosis factor-" receptor 1
(TNFR1) complex upon stimulation and known to play a crucial role in the receptor-induced
NF-!B activation. Interaction of RIP1 with the scaffold protein Hsp90 protects the adaptor
kinase from proteasome-dependent degradation. We showed that pretreatment of L929
fibrosarcoma cells with the Hsp90 inhibitor geldanamycin, induces a shift of TNF-induced
necrosis to apoptosis, suggesting a crucial role of RIP1 also in necrotic signaling. Using an
RNA interference approach, we demonstrate that RIP1 is crucial for the initiation of necrosis.
Moreover, retroviral transduction of kinase-death mutants shows that RIP1-induced necrosis
is dependent on its kinase activity. The importance of RIP1 has also been shown in FasL- and
dsRNA-induced caspase-independent cell death. Analogous to the formation of the
apoptosome, one can propose the formation of a “necrosome-complex” in which the
activation of RIP1 is a crucial event. We are currently trying to unravel the activation
mechanism of RIP1 and how RIP1 recruitment finally triggers downstream execution
mechamisms.
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