TY - JOUR
T1 - Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis
AU - Gitego, Nadege
AU - Agianian, Bogos
AU - Mak, Oi Wei
AU - Kumar MV, Vasantha
AU - Cheng, Emily H.
AU - Gavathiotis, Evripidis
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-44084-3
DO - 10.1038/s41467-023-44084-3
M3 - Article
C2 - 38104127
AN - SCOPUS:85179924063
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 8381
ER -