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A New Paradigm for BCL-2 Proteins: tBID Can Directly Trigger Cell Death

tBID can mediate mitochondrial permeabilisation in apoptosis on its own, opening up new opportunities for designing effective treatment strategies in anti-bacterial immunity and cancer therapy.

Apoptosis is the process of programmed cell death, used by the body since early development and throughout one’s life to discard unwanted cells. For instance, the cells between the fingers of a developing hand are instructed to die during embryonic development. Apoptosis also plays a crucial role in maintaining tissue balance and eliminating damaged or redundant cells in the body that would otherwise lead to a range of diseases. Accordingly, impaired apoptosis could lead to uncontrolled cell division and has been linked to autoimmune diseases, cancer, heart failure, and neurological disorders, hence its importance in research for treatments and preventive therapeutics.

During apoptosis, the BCL-2 family protein tBID triggers apoptosis by activating BAX and BAK, and blocking anti-apoptotic BCL-2 members, which promote mitochondrial permeabilisation. However, a recent discovery by Professor Dr. Ana Garcia-Saez and her colleagues at the University of Cologne’s CECAD Cluster of Excellence for Aging Research has shown that tBID, which was previously thought to be a mere signal transducer, can also induce apoptosis on its own, opening a new door to developing more effective therapies to treat malignant cells.

While BCL-2 proteins are generally essential for self-determined apoptosis of cells and tissue balance, many of the proteins in this family have overlapping functions, thereby preventing scientists from studying the specific functions of individual proteins. Noticing this knowledge gap, Garcia-Saez and her team set out to characterise the roles of the various family members. By studying cell lines that lack most of the BCL-2 proteins, the researchers were finally able to determine the role of tBID – it can mediate mitochondrial permeabilisation independently of BAX and BAK, which results in the release of cytochrome c and mitochondrial DNA, leading to caspase activation and apoptosis.

Upon closer analysis using cutting-edge microscopy, the team examined the effects of tBID at the mitochondrial membrane and reported that this previously unrecognised activity of tBID depends on α-helix 6, which is homologous to the pore-forming regions of BAX and BAK, and can be inhibited by pro-survival BCL-2 proteins. Most importantly, activating tBID was also observed to help fight cellular infection by the bacterium Shigella flexneri and has therapeutic potential to kill venetoclax-resistant leukaemia cells.

“For us, it was amazing to see that proteins which are quite well known still surprise us after four decades. The realisation that a protein that was considered a signal transducer for 20 years has an effector function under certain conditions is mind-blowing,” commented Garcia-Saez.

In future, this newly discovered function of tBID could be exploited in developing effective, targeted medicine. “For example, activating tBID could induce apoptosis when other known apoptosis signalling pathways fail or lack the proteins that carry it out,” said Garcia-Saez. “Activating tBID could also help with Shigella infections, where the proteins that usually induce apoptosis are not activated.” [APBN]

Source: Flores-Romero et al. (2021). BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. The EMBO Journal, e108690.