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

Jin Woo Kim, Eui Ju Choi, Cheol O. Joe

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86 Citations (Scopus)


The two opposite signaling pathways that stimulate NF-κB 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-κB activation. The uncleavable RIP(D324A) mutant was less apoptotic, but its ability to activate NF-κB activation was greater than the wild type counterpart. Ectopic expression of the pro-apoptotic C-terminal fragment of RIP inhibited TNF-induced NF-κB activation by suppressing the activity of I-κB kinaseβ (IKKβ) which phosphorylates 1-kB, an inhibitor of NF-κB, 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-κB activation, and thereby amplifies the activation of caspase-8 which initiates the downstream apoptotic events.

Original languageEnglish
Pages (from-to)4491-4499
Number of pages9
Issue number39
Publication statusPublished - 2000 Sept 14

Bibliographical note

Funding Information:
We appreciate Dr David Goeddel's (Tularik Inc., USA) provision of various cDNA clones. We thank Dr Brian Seed (Harvard Medical School, USA) for providing the RIP deficient cell line. This work was supported in part by a grant (95-0401-06-3) from the Korea Science and Engineering Foundation (CO Joe) and a grant from the Creative Research Initiatives Program of the Korea Ministry of Science and Technology (E-J Choi).


  • Apoptosis
  • Caspase-8
  • I-κB kinase
  • NF-κB activation
  • RIP

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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