A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway.
BRE, brain and reproductive organ-expressed 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-alpha-induced activation of NF-kappaB. Here we show that BRE also binds to another death receptor, Fas, and upon overexpression conferred resistance to apoptosis induced by TNF-alpha, 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-alpha, 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.
Clinical Immunology Unit and Sir Y. K. Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territory, Hong Kong Special Administrative Region, China.
Qing
Q
Li
Arthur Kar-Keung
AK
Ching
Ben Chung-Lap
BC
Chan
Stephanie Ka-Yee
SK
Chow
Pak-Leong
PL
Lim
Tony Cheong-Yip
TC
Ho
Wai-Ki
WK
Ip
Chun-Kwok
CK
Wong
Christopher Wai-Kei
CW
Lam
Kenneth Ka-Ho
KK
Lee
John Yeuk-Hon
JY
Chan
Yiu-Loon
YL
Chui
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
C091514:BABAM2 protein, human; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D005047:Etoposide; D003513:Cycloheximide