BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins

Abstract

Two major pathways for induction of apoptosis have been identified-intrinsic and extrinsic. The extrinsic pathway is represented by tumor necrosis factor family receptors, which utilize protein interaction modules known as death domains and death effector domains (DEDs) to assemble receptor signaling complexes that recruit and activate certain caspase-family cell death proteases, namely procaspases-8 and -10. The intrinsic pathway for apoptosis involves the participation of mitochondria, which release caspase-activating proteins. Bcl-2 family proteins govern this mitochondria-dependent apoptosis pathway, with proteins such as Bax functioning as inducers and proteins such as Bcl-2 and Bcl-X L serving as suppressors of cell death. An apoptosis regulator, BAR, was identified by using a yeast-based screen for inhibitors of Bax-induced cell death. The BAR protein contains a SAM domain, which is required for its interactions with Bcl-2 and Bcl-X L and for suppression of Bax-induced cell death in both mammalian cells and yeast. In addition, BAR contains a DED-like domain responsible for its interaction with DED-containing procaspases and suppression of Fas-induced apoptosis. Furthermore, BAR can bridge procaspase-8 and Bcl-2 into a protein complex. The BAR protein is anchored in intracellular membranes where Bcl-2 resides. BAR therefore may represent a scaffold protein capable of bridging two major apoptosis pathways.

Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia

“…Bcl 2 and Bax are implicated as anti-apoptotic and pro-apoptotic factors [Zhang et al, 2000]. The results presented in this study indicates that ROS is responsible for the downregulation of Bcl 2 , upregulation of Bax genes, and activation of caspase-9 in Hcy-induced MVEC apoptosis.…”

Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways

“…To this end, we performed an immunoblot analysis of human normal tissue samples using a BAR-specific rabbit antiserum, previously described. 11 BAR expression was highest by far in brain, with moderate expression in small intestine, weak expression in testes, and only faint expression in liver and skeletal muscle ( Figure 1a). No signal was detected in heart, kidney, lung, and spleen.…”

“…To examine BAR localization in more detail, we stably transfected the rat nigrostriatal cell line CSM 14.1 and the human astrocytoma cell line LN18 with a truncated version of BAR lacking its N-terminal RING domain, BAR(DR). Removal of the RING domain of BAR has been shown to prevent proteasome-dependent degradation of the protein, 11 allowing greater protein accumulation. The generation of these cell lines served as a useful model for expression and functional studies since: (i) BAR-transfected CSM cells allow the study of BAR localization and function in cells of neuronal origin, while BAR-transfected astrocytic LN18 cells serve as a control cell line for possible neuron-specific effects; and (ii) the epitopetagged, ectopically expressed BAR protein allows detection by two independent antibodies, anti-BAR and anti-myc.…”

“…11 To confirm that protection of neuronal cells from diverse cell death stimuli can be achieved by full-length BAR as well as BARDR, we transiently transfected CSM cells with a plasmid encoding wildtype BAR or the empty expression vector together with a GFP-encoding plasmid. After performing similar treatments as shown in Figure 4 In addition to cell death, we examined the effects of BAR expression on caspase activation.…”

“…10 The bifunctional apoptosis inhibitor (BAR) is a multidomain protein that was first discovered as an inhibitor of Bax-induced cell death. 11 BAR is capable of inhibiting apoptosis induced by TNF-family death receptors ('extrinsic pathway') as well as mitochondria-dependent apoptosis ('intrinsic pathway'). Interaction of BAR with Bcl-2 or Bcl-X L via a SAM domain may contribute to the antiapoptotic properties of BAR.…”