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

Oncogene volume 19, pages 4491–4499 (2000)Cite this article

Abstract

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 RIPD324A 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 I-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.

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Abbreviations

PKC:

protein kinase C

PAK:

p21-activated protein kinase

MEKK1:

MEK kinase 1

TNF:

tumor necrosis factor

TNFR:

TNF receptor

FADD:

Fas associated death domain

TRADD:

TNF receptor associated death domain

RIP:

receptor interacting protein

DISC:

death inducing signal complex

NF-κB:

nuclear factor κB

TRAF:

TNF receptor associating factor

JNK:

c-Jun N-terminal kinase

KD:

kinase domain

ID:

intermediate domain

DD:

death domain

NTF:

N-terminal fragment

CTF:

C-terminal fragment

IKK:

I-κB kinase

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea

    Jin Woo Kim & Cheol O Joe

  2. National Creative Research Initiative for Cell Death, Graduate School of Biotechnology, Korea University, Seoul 156-701, Korea

    Jin Woo Kim & Eui-Ju Choi

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Kim, J., Choi, EJ. & Joe, C. Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP. Oncogene 19, 4491–4499 (2000). https://doi.org/10.1038/sj.onc.1203796

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