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.