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.
Photo by Louis Reed on Unsplash
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.
Read the Original
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.
You can read the full text:
The following have contributed to this page