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

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

doi:10.1038/sj.onc.1203796

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

95 Citations (Scopus)

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 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 language	English
Pages (from-to)	4491-4499
Number of pages	9
Journal	Oncogene
Volume	19
Issue number	39
DOIs	https://doi.org/10.1038/sj.onc.1203796
Publication status	Published - 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).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

Access to Document

10.1038/sj.onc.1203796

Cite this

@article{b958447673fd4adca2a51c2cc3881f24,

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

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 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.",

keywords = "Apoptosis, Caspase-8, I-κB kinase, NF-κB activation, RIP",

author = "Kim, \{Jin Woo\} and Choi, \{Eui Ju\} and Joe, \{Cheol O.\}",

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).",

year = "2000",

month = sep,

day = "14",

doi = "10.1038/sj.onc.1203796",

language = "English",

volume = "19",

pages = "4491--4499",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Springer Nature",

number = "39",

}

TY - JOUR

T1 - Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP

AU - Kim, Jin Woo

AU - Choi, Eui Ju

AU - Joe, Cheol O.

N1 - 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).

PY - 2000/9/14

Y1 - 2000/9/14

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Caspase-8

KW - I-κB kinase

KW - NF-κB activation

KW - RIP

UR - https://www.scopus.com/pages/publications/0034648648

U2 - 10.1038/sj.onc.1203796

DO - 10.1038/sj.onc.1203796

M3 - Article

C2 - 11002422

AN - SCOPUS:0034648648

SN - 0950-9232

VL - 19

SP - 4491

EP - 4499

JO - Oncogene

JF - Oncogene

IS - 39

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this