Abstract
The intrinsic pathway of apoptotic cell death is mainly mediated by the BCL-2-associated X (BAX) protein through permeabilization of the mitochondrial outer membrane (MOM) and the concomitant release of cytochrome c into the cytosol. In healthy, non-apoptotic cells, BAX is predominantly localized in the cytosol and exhibits a dynamic shuttle cycle between the cytosol and the mitochondria. Thus, the initial association with mitochondria represents a critical regulatory step enabling BAX to insert into MOMs, promoting the release of cytochrome c and ultimately resulting in apoptosis. However, the molecular mode of how BAX associates with MOMs and whether a cellular regulatory mechanism governs this process is poorly understood. Here we show that in both primary tissues and cultured cells, the association with MOMs and the proapoptotic action of BAX is controlled by its S-palmitoylation at Cys-126. A lack of BAX palmitoylation reduced BAX mitochondrial translocation, BAX oligomerization, caspase activity and apoptosis. Furthermore, ectopic expression of specific palmitoyl transferases in cultured healthy cells increases BAX S-palmitoylation and accelerates apoptosis, whereas malignant tumor cells show reduced BAX S-palmitoylation consistent with their reduced BAX-mediated proapoptotic activity. Our findings suggest that S-palmitoylation of BAX at Cys126 is a key regulatory process of BAX-mediated apoptosis.
Highlights
During apoptosis BAX is inserted in the mitochondrial outer membrane (MOM) by a C-terminal tail anchor (TA).[1]
Unlike the majority of TA proteins, including antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL and the proapoptotic Bcl-2 family member BAK that are constitutively bound to their target membranes including mitochondrial and/or ER membranes, BAX in its monomeric inactive state predominantly appears in the cytosol of non-apoptotic cells.[16]
To elucidate the molecular mechanism controlling the transit of BAX to and from mitochondria in response to apoptotic stimuli, we investigated lipid modification of BAX and used acyl biotin-exchange (ABE) chemistry.[31]
Summary
During apoptosis BAX is inserted in the mitochondrial outer membrane (MOM) by a C-terminal tail anchor (TA).[1]. The structural and functional related proapoptotic BCL-2 protein BID exhibits striking similarities to BAX including the translocation to the MOM In their inactive state both proteins show a predominantly cytosolic localization and accumulate at the mitochondria upon apoptosis induction. For proteins containing transmembrane segements,[21,22,23,24,25] S-palmitoylation is suggested to change the tilt of the transmembrane segments within the bilayer or alter its conformation,[26] thereby promoting protein– protein interaction and complex formation.[25,27,28,29] On the basis of its ability to control the distribution and the function of a number of transmembrane- and membrane-associated proteins (e.g. associated with ER), here we asked whether S-palmitoylation of BAX could impact on the molecular switch regulating the dynamic and reversible equilibrium between cytosolic and mitochondrial BAX
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