A Death Receptor-associated Anti-apoptotic Protein, BRE, Inhibits Mitochondrial Apoptotic Pathway
BRE, b rain and r eproductive organ- e xpressed protein, was found previously to bind the intracellular juxtamembrane domain of a ubiquitous death receptor, tumor necrosis factor receptor 1 (TNF-R1), and to down-regulate TNF-α-induced activation of NF-κB. Here we show that BRE also binds to anothe...
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Published in | The Journal of biological chemistry Vol. 279; no. 50; pp. 52106 - 52116 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
10.12.2004
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Subjects | |
Online Access | Get full text |
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Summary: | BRE, b rain and r eproductive organ- e xpressed protein, was found previously to bind the intracellular juxtamembrane domain of a ubiquitous death receptor, tumor
necrosis factor receptor 1 (TNF-R1), and to down-regulate TNF-α-induced activation of NF-κB. Here we show that BRE also binds
to another death receptor, Fas, and upon overexpression conferred resistance to apoptosis induced by TNF-α, anti-Fas agonist
antibody, cycloheximide, and a variety of stress-related stimuli. However, down-regulation of the endogenous BRE by small
interfering RNA increased apoptosis to TNF-α, but nottoetoposide, indicating that the physiological antiapoptotic role of
this protein is specific to death receptor-mediated apoptosis. We further demonstrate that BRE mediates antiapoptosis by inhibiting
the mitochondrial apoptotic machinery but without translocation to the mitochondria or nucleus or down-regulation of the cellular
level of truncated Bid. Dissociation of BRE rapidly from TNF-R1, but not from Fas, upon receptor ligation suggests that this
protein interacts with the death inducing signaling complex during apoptotic induction. Increased association of BREwith phosphorylated,
sumoylated, and ubiquitinated proteins after death receptor stimulation was also detected. We conclude that in contrast to
the truncated Bid that integrates mitochondrial apoptosis to death receptor-triggered apoptotic cascade, BRE inhibits the
integration. We propose that BRE inhibits, by ubiquitination-like activity, components in or proximal to the death-inducing
signaling complexes that are necessary for activation of the mitochondria. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M408678200 |