The balance between cell proliferation and cell death plays a key role in maintaining cell homeostasis throughout life (1). In cancer cells, the escape of apoptosis is generally correlated with a deregulation of the activity of BCL-2 family proteins, which are thus potential therapeutic targets (2).
BCL-2 proteins are mainly known for their control of mitochondrial outer membrane permeabilization (MOMP) (3). However, we and others have shown that besides mitochondria, BCL-2-related proteins also reside at the endoplasmic reticulum (ER) (4-7). ER-based BCL-2 homologs control the intracellular Ca2+ fluxes, monitoring MOMP remotely or even exerting non-MOMP related functions such as cell migration, mitochondrial metabolism or ever gene expression (7). Despite these observations, many unanswered questions regarding the multifunctionality of BCL-2 proteins remain to be solved.