Abstract
BFL1 is a relatively understudied member of the BCL2 protein family which has been implicated in the pathogenesis and chemoresistance of a variety of human cancers, including hematological malignancies and solid tumours. BFL1 is generally considered to have an antiapoptotic function, although its precise mode of action remains unclear. By quantitatively analyzing BFL1 action in synthetic membrane models and in cells, we found that BFL1 inhibits apoptosis through three distinct mechanisms which are similar but not identical to those of BCLXL, the paradigmatic antiapoptotic BCL2 family protein. Strikingly, alterations in lipid composition during apoptosis activate a prodeath function of BFL1 that is based on noncanonical oligomerization of the protein and breaching of the permeability barrier of the outer mitochondrial membrane (OMM). This lipid-triggered prodeath function of BFL1 is absent in BCLXL and also differs from that of the apoptotic effector BAX, which sets it apart from other BCL2 family members. Our findings support a new model in which BFL1 modulates apoptosis through a bifunctional and multimodal mode of action that is distinctly regulated by OMM lipids compared to BCLXL.
Highlights
Apoptotic programmed cell death plays an essential role in many human physiological processes and pathologies [1]
We report that the apoptosis-related lipids cardiolipin (CL) and oxidized CL (CLox) unleash a prodeath function in BFL1, but not in BCLXL, that is based in a noncanonical membranepermeabilizing activity of the protein
Similar to BCLXL, GFP-BFL1 itself showed a decrease in mitochondrial fluorescence by Fluorescence Loss In Photobleaching (FLIP) following a first-order kinetic, and BAX overexpression accelerated the FLIP rate of mitochondrial GFP-BFL1 (Fig. S1d)
Summary
Apoptotic programmed cell death plays an essential role in many human physiological processes and pathologies [1]. Despite the relevance of the above classification, important questions remain regarding the molecular mechanisms by which BCL2 family proteins exert their biological function. BFL1 modulates apoptosis at the membrane level through a bifunctional and multimodal mechanism showing. Display a hydrophobic groove centered on the BH1 motif that serves as a receptor-site for binding BH3 motifs of ligand partners [2]. In addition to this canonical BH3: groove binding interface, other noncanonical interaction surfaces have been identified in a variety of BCL2 family proteins. Two prominent examples are the BH4 and TA motifs of BCL2 and BCLXL, which can mediate heteromeric interactions with BAX implicated in apoptosis
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