Novel mechanisms of endophilin B1-mediated membrane remodeling drives Bax-dependent cell death

During apoptosis, cell death protein Bax translocates to the mitochondria where it triggers membrane permeabilization and release of cytochrome c. Exactly how Bax is activated remains obscure and constitutes a major outstanding question. Knockdown of BAR protein endophilin B1 causes inhibition of cell death.

BAR proteins induce membrane curvature, and thereby regulate a wide variety of membrane trafficking events.

Loss of endophilin B1 is seen in many forms of cancer, suggesting that endophilin B1 serves a critical tumor suppressor role in the cell by controlling cell death. Exactly how endophilin B1 regulates these events, and how its membrane activity is regulated is not understood. Endophilin B1 assembles into protein scaffolds on lipid membranes enriched with phospholipid cardiolipin.

Endophilin B1 recruits Bax to these mitochondria-like membranes, facilitates their permeabilization and controls the organization of cardiolipin in HEK293 cells.

Bax, in turn causes oligomerization of endophilin B1 although we find no evidence of direct endophilin B1-Bax interactions in solution.

We speculate the endophilin B1 controls cell death by controlling the organization of membrane lipids, Bax recruitment and assembly, and ultimately membrane permeabilization, while Bax and other binding partners and membrane lipids regulate the activity of endophilin B1. Thus, endophilin B1, local lipids and binding partners cooperate to coordinate mitochondrial cell death.