Journal
EMBO JOURNAL
Volume 41, Issue 2, Pages -Publisher
WILEY
DOI: 10.15252/embj.2021108690
Keywords
apoptosis; BCL-2 proteins; mitochondrial permeabilization; pore formation
Categories
Funding
- Deutsche Forschungsgesellschaft (DFG, German Research foundation) [269925409]
- European Research Council (ERC) [817758]
- Austrian Science Fund, FWF [I-3271]
- [414786233]
- European Research Council (ERC) [817758] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
This study reveals a previously unrecognized activity of tBID in mediating mitochondrial permeabilization independently of BAX and BAK, which has physiological relevance in immune response and cancer therapy. This novel function of tBID is dependent on a specific helix structure and can be blocked by anti-apoptotic proteins, providing potential implications for therapeutic intervention in bacterial infections and cancer treatment.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available