Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis
Abstract The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane perme...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44084-3 |
| _version_ | 1797388211383697408 |
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| author | Nadege Gitego Bogos Agianian Oi Wei Mak Vasantha Kumar MV Emily H. Cheng Evripidis Gavathiotis |
| author_facet | Nadege Gitego Bogos Agianian Oi Wei Mak Vasantha Kumar MV Emily H. Cheng Evripidis Gavathiotis |
| author_sort | Nadege Gitego |
| collection | DOAJ |
| description | Abstract The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in apoptosis execution. Previous studies reported two inactive conformations of cytosolic BAX, a monomer and a dimer, however, it remains unclear how they regulate BAX. Here we show that, surprisingly, cancer cell lines express cytosolic inactive BAX dimers and/or monomers. Expression of inactive dimers, results in reduced BAX activation, translocation and apoptosis upon pro-apoptotic drug treatments. Using the inactive BAX dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic BAX dimers and prompts cells to apoptosis either alone or in combination with BCL-2/BCL-XL inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive BAX dimer in resistance to apoptosis and demonstrate a strategy to potentiate BAX-mediated apoptosis. |
| first_indexed | 2024-03-08T22:37:31Z |
| format | Article |
| id | doaj.art-887f3cce28c94c2a981f814af8621aef |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:31Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-887f3cce28c94c2a981f814af8621aef2023-12-17T12:23:11ZengNature PortfolioNature Communications2041-17232023-12-0114112010.1038/s41467-023-44084-3Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosisNadege Gitego0Bogos Agianian1Oi Wei Mak2Vasantha Kumar MV3Emily H. Cheng4Evripidis Gavathiotis5Department of Biochemistry, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineDepartment of Biochemistry, Albert Einstein College of MedicineHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterDepartment of Biochemistry, Albert Einstein College of MedicineAbstract The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in apoptosis execution. Previous studies reported two inactive conformations of cytosolic BAX, a monomer and a dimer, however, it remains unclear how they regulate BAX. Here we show that, surprisingly, cancer cell lines express cytosolic inactive BAX dimers and/or monomers. Expression of inactive dimers, results in reduced BAX activation, translocation and apoptosis upon pro-apoptotic drug treatments. Using the inactive BAX dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic BAX dimers and prompts cells to apoptosis either alone or in combination with BCL-2/BCL-XL inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive BAX dimer in resistance to apoptosis and demonstrate a strategy to potentiate BAX-mediated apoptosis.https://doi.org/10.1038/s41467-023-44084-3 |
| spellingShingle | Nadege Gitego Bogos Agianian Oi Wei Mak Vasantha Kumar MV Emily H. Cheng Evripidis Gavathiotis Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis Nature Communications |
| title | Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis |
| title_full | Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis |
| title_fullStr | Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis |
| title_full_unstemmed | Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis |
| title_short | Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis |
| title_sort | chemical modulation of cytosolic bax homodimer potentiates bax activation and apoptosis |
| url | https://doi.org/10.1038/s41467-023-44084-3 |
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