ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage.
Programmed cell death is essential for the development and maintenance of cellular homeostasis, and its deregulation results in a variety of pathologic conditions. The BCL-2 family of proteins is a group of evolutionarily conserved regulators of cell death that operate at the mitochondrial membrane to control caspase activation. This family is comprised both of antiapoptotic and proapoptotic members, in which a subset of proapoptotic members, called BH3-only proteins, acts as upstream activators of the core proapoptotic pathway. In addition to their known role at the mitochondria, different BCL-2-related proteins are located to the endoplasmic reticulum (ER) membrane, where new functions have been recently proposed. In this review, evidence is presented indicating that members of the BCL-2 protein family are contained in multiprotein complexes at the ER, regulating diverse cellular processes including autophagy, calcium homeostasis, the unfolded-protein response, ER membrane remodeling, and calcium-dependent cell death. Thus, BCL-2-related proteins are not only the "death gateway" keepers, but they also have alternative functions in essential cellular processes.
Hetz
Claudio A
CA
Department of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile and the FONDAP Center for Molecular Studies of the Cell (CEMC), Santiago, Chile. chetz@med.uchile.cl
D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005544:Forecasting; D006801:Humans; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2