chapter  7
‘ВНЗ-domain-only’ proteins as multidomain protein activators
Pages 5

The ‘ВНЗ-domain-only proteins’ appear to function mainly through activation of the multidomain proteins. Bid was shown a few years ago to provide a shunt between the two apoptotic pathways, the death receptor and the mitochondrial pathway (Schmitz et al, 1999). In some cell types (so-called type 2 cells), Fasinduced apoptosis results in a low activation of caspase-8 at the membrane recep­ tor. This appears to be insufficient for activation of the direct caspase pathway. In these cells, caspase-8 cleaves Bid, generating a C-terminal fragment (tcBid) that interacts with Bax or Bak, and results in activation of these proteins and the mito­ chondrial pathway. This mechanism functions as an amplification loop to enhance the apoptotic intracellular signaling cascade. tcBid has been shown to translocate to the mitochondria, where it is found in apoptotic cells (Gross et al, 1999b). Whether the protein colocalizes only with Bax or Bak or whether it has an inde­ pendent activity at the mitochondrial membrane still remains unclear. Fibroblasts from Bax and Bak double-deficient mice were completely resistant to tcBidinduced cell death. The mice also showed a pronounced increased resistance to hepatocyte damage after treatment with anti-Fas antibodies (Wei et al, 2001). At least in these two systems, Bid acts through activation of the multidomain proteins. However, in artificial membrane systems, tcBid has a membrane-destabilizing effect (Kudla et al, 2000). Whether such an activity is also present under physio­ logic conditions remains to be elucidated. It is conceivable that tcBid, through destabilization of the mitochondrial membrane, could facilitate insertion of the multidomain proteins and thereby promote channel formation.