Translocation of Full-length Bid to Mitochondria during Anoikis

Abstract

Epithelial cells require adhesion to the extracellular matrix for survival, and in the absence of adhesion they undergo apoptosis (anoikis). This is distinct from apoptosis induced by extracellular death ligands, such as tumor necrosis factor, which result in direct activation of caspase 8. Bid is a member of the BH3-only subfamily of the Bcl-2 proteins and is important for most cell types to apoptose in response to Fas and tumor necrosis factor receptor activation. Caspase 8 cleaves full-length Bid, resulting in truncated p15 tBid. p15 tBid is potently apoptotic and activates the multidomain Bcl-2 protein, Bax, resulting in release of cytochrome c from mitochondria. We have previously shown that Bax rapidly translocates from the cytosol to mitochondria following loss of adhesion and that this is required for anoikis. We have now examined the role of Bid in anoikis. Bid translocates to mitochondria with identical kinetics as Bax. Although Bid is required for anoikis, it does not require proteolytic cleavage by caspase 8. Furthermore, it does not require Bid to interact directly with other Bcl-2 family proteins, such as Bax. Our data indicate that Bid is important for regulating apoptosis via the intrinsic pathway and has implications for how Bid may fulfill that role.

Anoikis: an emerging hallmark in health and diseases

“…The final event is the activation of the effector caspase-3 and execution of the apoptotic process [11][12][13]. Anoikis due to the intrinsic pathway is mainly initiated by Bim, although a role has been proposed also for Bid [14]. Bim is activated following detachment of cells from the ECM and rapidly promotes the assembly of Bax-Bak oligomers within the OMM [15,16].…”

“…Caspase-8 can now independently activate effector caspases (type I extrinsic anoikis) or cleave the BH3-only protein Bid (type II extrinsic anoikis) (Figure 1) [7]. t-Bid (truncated-Bid) promote mitochondrial cytochrome c release and assembly of the apoptosome [32][33][34][35][36].…”

BCL2 family in DNA damage and cell cycle control

“…56 Full-length BID is also capable of translocation to the mitochondria in at least one case facilitated by other proteins such as PACS2. [57][58][59] At the mitochondria, full-length BID has been shown to potentiate cell death following certain apoptotic signals, suggesting that caspase cleavage is not an absolute requirement for activating BID's proapoptotic function. 58,60 Recent studies indicate that activation of BID's prodeath activity may be negatively regulated by phosphorylation.…”

Multistep and multitask Bax activation

“…This cell death mechanism is likely to kill cells that detached including migrating cells in order to avoid metastasis (Frisch and Screaton, 2001). After experimental cell detachment, Bax migrates to mitochondria in a tBid-independent manner (Valentijn and Gilmore, 2004). At this point, apoptotic factors are not released and cells can be still be rescued (Gilmore et al, 2000).…”