부산대학교 도서관

During apoptosis, the BCL‐2‐family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti‐apoptotic BCL‐2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore‐forming regions of BAX and BAK, and can be blocked by pro‐survival BCL‐2 proteins. Importantly, tBID‐mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL‐2 proteins, with implications for anti‐bacterial immunity and cancer therapy. SYNOPSIS: The BCL‐2‐family protein tBID promotes mitochondrial permeabilization in apoptosis by activating BAX and BAK and by blocking the anti‐apoptotic BCL‐2 members. Here, tBID is found to mediate mitochondrial permeabilization and apoptosis also in the absence of BAX and BAK. tBID directly induces mitochondrial permeabilization and release of cytochrome c, SMAC and mitochondrial DNA.tBID effector function requires its helix 6, homologous to the pore‐forming regions of BAX and BAK, and can be blocked by pro‐survival BCL‐2 proteins.BAX/BAK‐independent mitochondrial permeabilization by tBID is important for SMAC release during anti‐Shigella immune responses.TRAIL‐induced BID cleavage can be exploited to kill leukaemia cells with acquired venetoclax resistance due to loss of active BAX and BAK. [ABSTRACT FROM AUTHOR]