Integrating stress signals at the endoplasmic reticulum: The BCL-2 protein family rheostat

• Published in: Biochimica et biophysica acta Vol. 1813; no. 4; pp. 564 - 574
• Main Authors: Rodriguez, Diego, Rojas-Rivera, Diego, Hetz, Claudio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2011
• Subjects: Animals; Apoptosis; BCL-2 family; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Humans; Mitochondria - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Stress, Physiological; Unfolded protein response; IP3R; JNK; MCL-1; RyR; PERK; PTP; TMBIM; Unfolded protein response; NF-κB; UPR; AIP1; PTP-1B; BCL-2 family; TRAF2; PP2A; SERCA; ER; JIK; eIF2α; BI-1; IRE1α; ATF6; XBP-1; Endoplasmic reticulum; ERK
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2010.11.012

The assembling of distinct signaling protein complexes at the endoplasmic reticulum (ER) membrane controls several stress responses related to calcium homeostasis, autophagy, ER morphogenesis and protein folding. Diverse pathological conditions interfere with the function of the ER altering protein folding, a condition known as “ER stress”. Adaptation to ER stress depends on the activation of the unfolded protein response (UPR) and protein degradation pathways such as autophagy. Under chronic or irreversible ER stress, cells undergo apoptosis, where the BCL-2 protein family plays a crucial role at the mitochondria to trigger cytochrome c release and apoptosome assembly. Several BCL2 family members also regulate physiological processes at the ER through dynamic interactomes. Here we provide a comprehensive view of the roles of the BCL-2 family of proteins in mediating the molecular crosstalk between the ER and mitochondria to initiate apoptosis, in addition to their emerging functions in adaptation to stress, including autophagy, UPR, calcium homeostasis and organelle morphogenesis. We envision a model where BCL-2-containing complexes may operate as stress rheostats that, beyond their known apoptosis functions at the mitochondria, determine the amplitude and kinetics of adaptive responses against ER-related injuries. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. ▶ BCL-2 family of proteins control apoptosis at the mitochondria. ▶ Some BCL-2 family members regulate stress responses from the ER. ▶ Dynamic BCL-2 proteins-containing complexes regulate adaptation to stress. ▶ BCL-2 family members modulates IRE1α by forming part of the UPRosome.