Hexokinases inhibit death receptor–dependent apoptosis on the mitochondria
| Autor: | Frank Edlich, Franziska Fimm-Todt, Martin van der Laan, Joachim Lauterwasser, Hugo Falquez-Medina, Katelyn O'Neill, Günther Jahreis, Xu Luo, Aline Oelgeklaus, Kathrin Funk, Ralf M. Zerbes, Annabell Schreiner, Ramona Klesse |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Fas Ligand Protein Truncated BID Mitochondrion BCL-2 proteins Gene Expression Regulation Enzymologic Cell Line TNF-Related Apoptosis-Inducing Ligand chemistry.chemical_compound Hexokinase Humans Enzyme Inhibitors Receptor bcl-2-Associated X Protein Multidisciplinary Antibiotics Antineoplastic Activator (genetics) Chemistry BH3-only proteins apoptosis Cell Biology Biological Sciences Cell biology Anti-Bacterial Agents Mitochondria Cytosol bcl-2 Homologous Antagonist-Killer Protein Apoptosis Doxorubicin Cyclosporine Dactinomycin biological phenomena cell phenomena and immunity Gene Deletion |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance 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 the mitochondria into the cytosol. Hexokinase-dependent BCL-2 protein retrotranslocation can protect cells from apoptosis despite death receptor signaling. 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 proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival 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. |
| Databáze: | OpenAIRE |
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