How Do Hexokinases Inhibit Receptor-Mediated Apoptosis?

SIMPLE SUMMARY: In multicellular animals, cells autonomously respond to lethal stress by inducing cell death programs. The most common regulated cell death is apoptosis. Cells protect their neighbors from damage by their cell contents or infection through this process. Apoptosis can occur as a result of intrinsic stress or induced by surface receptors, for example, by immune cells. In most cases, receptor-mediated apoptosis also requires the intrinsic signaling pathway. Intrinsic apoptosis is controlled by proteins of the B-cell lymphoma 2 (BCL-2) family. Pro-apoptotic BCL-2 proteins are inhibited by retrotranslocation from the mitochondria into the cytosol until the cell commits to apoptosis. Increasingly, discoveries show that BCL-2 proteins are regulated by proteins that are not themselves members of the BCL-2 family. Here, we discuss the selective inhibition of the link between death receptors activation and intrinsic apoptosis by hexokinases. These enzymes funnel glucose into the cellular metabolism. Independently, hexokinases retrotranslocate BCL-2 proteins and thereby protect cells from receptor-mediated apoptosis. ABSTRACT: The regulated cell death apoptosis enables redundant or compromised cells in ontogeny and homeostasis to remove themselves receptor-dependent after extrinsic signaling or after internal stress by BCL-2 proteins on the outer mitochondrial membrane (OMM). Mitochondrial BCL-2 proteins are also often needed for receptor-mediated signaling in apoptosis. Then, the truncated BH3-only protein BID (tBID) blocks retrotranslocation of the pro-apoptotic BCL-2 proteins BAX and BAK from the mitochondria into the cytosol. BAX and BAK in turn permeabilize the OMM. Although the BCL-2 proteins are controlled by a complex regulatory network, a specific mechanism for the inhibition of tBID remained unknown. Curiously, it was suggested that hexokinases, which channel glucose into the metabolism, have an intriguing function in the regulation of apoptosis. Recent analysis of transient hexokinase interactions with BAX revealed its participation in the inhibition of BAX and also BAK by retrotranslocation from mitochondria to the cytosol. In contrast to general apoptosis inhibition by anti-apoptotic BCL-2 proteins, hexokinase I and hexokinase 2 specifically inhibit tBID and thus the mitochondrial apoptosis pathway in response to death receptor signaling. Mitochondrial hexokinase localization and BH3 binding of cytosolic hexokinase domains are prerequisites for protection against receptor-mediated cell death, whereas glucose metabolism is not. This mechanism protects cells from apoptosis induced by cytotoxic T cells.