Abstract
Most intrinsic death signals converge into the activation of pro-apoptotic BCL-2 family members BAX and BAK at the mitochondria, resulting in the release of cytochrome c and apoptosome activation. Chronic endoplasmic reticulum (ER) stress leads to apoptosis through the upregulation of a subset of pro-apoptotic BH3-only proteins, activating BAX and BAK at the mitochondria. Here we provide evidence indicating that the full resistance of BAX and BAK double deficient (DKO) cells to ER stress is reverted by stimulation in combination with mild serum withdrawal. Cell death under these conditions was characterized by the appearance of classical apoptosis markers, caspase-9 activation, release of cytochrome c, and was inhibited by knocking down caspase-9, but insensitive to BCL-XL overexpression. Similarly, the resistance of BIM and PUMA double deficient cells to ER stress was reverted by mild serum withdrawal. Surprisingly, BAX/BAK-independent cell death did not require Cyclophilin D (CypD) expression, an important regulator of the mitochondrial permeability transition pore. Our results suggest the existence of an alternative intrinsic apoptosis pathway emerging from a cross talk between the ER and the mitochondria.
Highlights
Apoptosis is a conserved cell death mechanism essential for normal development and tissue homeostasis in multicellular organisms
We previously reported an impaired ability of BAX and BAK DKO murine embryonic fibroblasts (MEFs) to activate the endoplasmic reticulum (ER)
In this article we have identified experimental conditions where classical intrinsic death stimuli engage the mitochondrial apoptosis machinery in the absence of BAX, BAK and Cyclophilin D (CypD)
Summary
Apoptosis is a conserved cell death mechanism essential for normal development and tissue homeostasis in multicellular organisms. Pro-apoptotic BCL-2 family members can be further subdivided into more highly conserved, ‘‘multidomain’’ members displaying homology in the BH1, BH2 and BH3 domains (i.e. BAX and BAK), and the ‘‘BH3-only’’ members which contain a single BH domain critical for activation of apoptosis. The BH3-only proteins can be functionally separated into two subtypes: (i) activators (i.e. tBID, BIM, and PUMA) that directly engage BAX and BAK to trigger cytochrome c release, but are sequestered by anti-apoptotic BCL-2 molecules; and (ii) sensitizers or inactivators (i.e. BAD and NOXA) that only bind to and antagonize anti-apoptotic BCL-2 members to release activator BH3-only proteins (examples in [7,8,9,10,11]). Differential binding to anti-apoptotic proteins may explain the action of activator and sensitizer/inactivator BH3-only proteins [12] or combination of both models [11,13,14]
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