Oncogene. 2000 Sep 14;19(39):4491-9.

Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP.External

Kim, J. W., Choi, E. J., Joe, C. O.,
--- - Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea.
The two opposite signaling pathways that stimulate NF-kappaB activation and apoptosis are both mediated by tumor necrosis factor receptor 1 (TNFR1) and its cytosolic associated proteins. In this study, we demonstrate that the proteolytic cleavage of receptor interacting protein (RIP) by caspase-8 during TNF-induced apoptosis abrogates the stimulatory role of RIP on TNF-induced NF-kappaB activation. The uncleavable RIPD324A mutant was less apoptotic, but its ability to activate NF-kappaB activation was greater than the wild type counterpart. Ectopic expression of the pro-apoptotic C-terminal fragment of RIP inhibited TNF-induced NF-kappaB activation by suppressing the activity of I-kappaB kinasebeta (IKKbeta) which phosphorylates I-kB, an inhibitor of NF-kappaB, and triggers its ubiquitin-mediated degradation. The C-terminal fragment of RIP also enhanced the association between TNFR1 and death domain proteins including TNFR1 associated death domain (TRADD) and Fas associated death domain (FADD), resulting in the activation of caspase-8 and stimulation of apoptosis. The present study suggest that the C-terminal fragment of RIP produced by caspase-8 activates death-inducing signaling complex (DISC), attenuates NF-kappaB activation, and thereby amplifies the activation of caspase-8 which initiates the downstream apoptotic events. Oncogene (2000) 19, 4491 - 4499.
PMID: 11002422External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD FADD Link RIP Co-Immunofluorescence staining HEK293 Not specified Not specified Human Not specified 11002422
DD FADD Link TNFR1 Co-immunoprecipitation Jurkat Not specified Not specified Not specified Not specified 11002422
DD RIP Link TNFR1 Co-immunoprecipitation Jurkat Human Not specified Not specified Not specified 11002422
DD TNFR1 Link TRADD Co-immunoprecipitation Jurkat Not specified Not specified Not specified Not specified 11002422
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
DD FADD Link RIP Propidium iodide staining Apoptosis (DISC) 11002422
DD RIP Link TNFR1 Propidium iodide staining Apoptosis (DISC) 11002422
(Link: click this icon to show interactions only between the two corresponding DDs)