BCL-2 family: integrating stress responses at the ER to control cell demise

In the last decade, the endoplasmic reticulum (ER) has emerged as a central organelle regulating the core mitochondrial apoptosis pathway. At the ER membrane, a variety of stress signals are integrated toward determining cell fate, involving a complex cross talk between key homeostatic pathways including the unfolded protein response, autophagy, calcium signaling and mitochondrial bioenergetics. In this context, key regulators of cell death of the BCL-2 and TMBIM/BI-1 family of proteins have relevant functions as stress rheostats mediated by the formation of distinct protein complexes that regulate the switch between adaptive and proapoptotic phases under stress. Here, we overview recent advances on our molecular understanding of how the apoptotic machinery integrates stress signals toward cell fate decisions upstream of the mitochondrial gateway of death.FONDECYT 3150113 1140549 FONDAP program 15150012 Millennium Institute P09-015-F European Commission RD MSCA-RISE 734749 Michael J Fox Foundation for Parkinson's Research - Target Validation grant 9277 FONDEF ID16I10223 D11E1007 US Office of Naval Research-Global (ONR-G) N62909-16-1-2003 U.S. Air Force Office of Scientific Research FA9550-16-1-0384 ALSRP Therapeutic Idea Award AL150111 Muscular Dystrophy Association 382453 CONICYT-Brazil 441921/2016-7 CONICYT fellowshi