BFL1 modulates apoptosis at the membrane level through a bifunctional and multimodal mechanism showing key differences with BCLXL.,Cell Death and Differentiation

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BFL1 modulates apoptosis at the membrane level through a bifunctional and multimodal mechanism showing key differences with BCLXL.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2018-12-18 , DOI: 10.1038/s41418-018-0258-5
Hector Flores-Romero _{1,

2} , Olatz Landeta _{1,

3} , Begoña Ugarte-Uribe _{2,

3} , Katia Cosentino ₂ , Miguel García-Porras ₁ , Ana J García-Sáez ₂ , Gorka Basañez ₁

Affiliation

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.

中文翻译：

BFL1通过双功能和多峰机制在膜水平上调节细胞凋亡，显示出与BCLXL的关键差异。

BFL1是BCL2蛋白家族中一个相对未被充分研究的成员，该家族已经参与了包括血液系统恶性肿瘤和实体瘤在内的多种人类癌症的发病机理和化学耐药性研究。尽管尚不清楚BFL1的确切作用方式，但通常认为它具有抗凋亡功能。通过定量分析合成膜模型和细胞中BFL1的作用，我们发现BFL1通过三种不同的机制抑制细胞凋亡，这些机制与范式抗凋亡BCL2家族蛋白BCLXL相似但不相同。令人惊讶的是，凋亡过程中脂质成分的变化激活了BFL1的前代功能，该功能基于蛋白质的非规范性寡聚和突破线粒体外膜（OMM）的通透性屏障。BCL1中不存在这种由脂质触发的BFL1促成胎功能，并且与凋亡效应因子BAX不同，后者使BFL1与其他BCL2家族成员区分开。我们的发现支持一种新的模型，其中BFL1通过双功能和多峰作用模式调节细胞凋亡，而BMMXL与BFLXL相比，BFL1受OMM脂质明显调节。

更新日期：2019-01-26

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