Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions

Young-Jae Nam; Kartik Mani; Anthony W Ashton; Chang-Fu Peng; Barath Krishnamurthy; Yukihiro Hayakawa; Peiyee Lee; Stanley J Korsmeyer; Richard N Kitsis

doi:10.1016/j.molcel.2004.08.020

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Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions

Journal article

Open access

Peer reviewed

Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions

Young-Jae Nam, Kartik Mani, Anthony W Ashton, Chang-Fu Peng, Barath Krishnamurthy, Yukihiro Hayakawa, Peiyee Lee, Stanley J Korsmeyer and Richard N Kitsis

Molecular cell, Vol.15(6), pp.901-912

09/24/2004

DOI: 10.1016/j.molcel.2004.08.020

PMID: 15383280

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Published (Version of record) Open Access

Abstract

Death-fold domains constitute an evolutionarily conserved superfamily that mediates apoptotic signaling. These motifs, including CARD (caspase recruitment domain), DD (death domain), and DED (death effector domain), are believed to exert their effects solely through homotypic interactions. Herein we demonstrate that the CARD-containing protein ARC engages in nontraditional death-fold interactions to suppress both extrinsic and intrinsic death pathways. The extrinsic pathway is disrupted by heterotypic interactions between ARC's CARD and the DDs of Fas and FADD, which inhibit Fas-FADD binding and assembly of the death-inducing signaling complex (DISC). The intrinsic pathway is antagonized by ARC-Bax binding, involving ARC's CARD and the Bax C terminus. This inhibits Bax activation and translocation to the mitochondria. Knockdown of endogenous ARC facilitates DISC assembly and triggers spontaneous Bax activation and apoptosis. Conversely, physiological levels of ARC suppress these events. These studies establish a critical role for nonhomotypic death-fold interactions in the regulation of apoptosis.

Adenoviridae - genetics

Amino Acid Motifs

Amino Acid Substitution

Animals

Apoptosis

bcl-2-Associated X Protein

Caspases - metabolism

Cell Line

Cells, Cultured

Chromatography, Gel

Death Domain Receptor Signaling Adaptor Proteins

fas Receptor - metabolism

Humans

Mice

Models, Biological

Myocytes, Cardiac - drug effects

Phenylalanine - metabolism

Precipitin Tests

Protein Structure, Tertiary

Proto-Oncogene Proteins - chemistry

Proto-Oncogene Proteins - metabolism

Proto-Oncogene Proteins c-bcl-2

Rats

Receptors, Tumor Necrosis Factor

Recombinant Fusion Proteins - metabolism

Two-Hybrid System Techniques

Details

Title: Subtitle: Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions
Creators: Young-Jae Nam - Albert Einstein College of Medicine
Kartik Mani - Albert Einstein College of Medicine
Anthony W Ashton - Albert Einstein College of Medicine
Chang-Fu Peng - Albert Einstein College of Medicine
Barath Krishnamurthy - Albert Einstein College of Medicine
Yukihiro Hayakawa - Albert Einstein College of Medicine
Peiyee Lee - Albert Einstein College of Medicine
Stanley J Korsmeyer - Harvard University
Richard N Kitsis - Albert Einstein College of Medicine
Resource Type: Journal article
Publication Details: Molecular cell, Vol.15(6), pp.901-912
DOI: 10.1016/j.molcel.2004.08.020
PMID: 15383280
ISSN: 1097-2765
eISSN: 1097-4164
Grant note: HL60665 / NHLBI NIH HHS GM 07491 / NIGMS NIH HHS HL61550 / NHLBI NIH HHS
Language: English
Date published: 09/24/2004
Academic Unit: Internal Medicine
Record Identifier: 9984695681502771

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