What is it about?

Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling the truncated BH3-only protein BID can activate the pro-apoptotic BCL-2 proteins BAX and BAK and trigger permeabilization of the mitochondria. BAX and BAK are inhibited by pro-survival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins, but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor-induced apoptosis on the mitochondria.

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Why is it important?

Receptor-ligand interactions on the cell surface or intrinsic stress signals can commit mammalian cells to apoptosis. In this study, we discover how hexokinases confer resistance to receptor-mediated apoptosis through specific inhibition of B-cell lymphoma 2 (BCL-2) proteins. Hexokinases retrotranslocate activator and effector BCL-2 proteins from mitochondria into the cytosol. Hexokinase-dependent BCL-2 proteins retrotranslocation can protect cells from apoptosis despite death receptor signaling.

Perspectives

Immune cells ideally transmit the signal to cancer cells to kill themselves. When this mechanism no longer functions properly, the organism could develop a tumor. We have discovered a new mechanism that prevents this natural cell death. Hexokinases interrupt the signal for regulated cell suicide. They recognize the signal molecule and transport it away from the site of action, the mitochondria. This allows tumor cells to bypass their suicide. This selective protective mechanism against apoptosis at the mitochondria could, among other things, play an important role in the elimination of cancer cells in particular by the immune system. These findings could prove useful in the development of more effective targeted cancer therapies.

Frank Edlich
University of Leipzig

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This page is a summary of: Hexokinases inhibit death receptor–dependent apoptosis on the mitochondria, Proceedings of the National Academy of Sciences, August 2021, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2021175118.
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