By Christina Towers, PhD
Apoptosis, or programmed cell death, is the result of an intricate cascade of signaling events that is initiated by extrinsic (death receptor mediated) and intrinsic (mitochondrial mediated) stimuli. Extrinsic apoptosis is initiated by ligand binding to death receptors followed by signaling cascades that activate caspase-8, also known as the initiator caspase. The effector caspase-3 can be activated by caspase-8, but is usually activated downstream of the intrinsic pathway, and often the extrinsic pathway will converge on the intrinsic for more efficient programmed cell death. Intrinsic signaling takes place on the mitochondrial membrane, where BH-3 only proteins activate mitochondrial outer membrane permeabilization (MOMP) and the release of mitochondrial proteins like cytochrome c. Subsequently, the apoptosome is formed by a complex of proteins that include cytochrome c to activate caspase-9, leading to the eventual activation of caspase-3. In contrast, autophagy is another tightly regulated cellular process that degrades damaged cytoplasmic material and recycles necessary building blocks that fuel metabolism. Stress can often induce autophagy, and cancer cells in particular can utilize this process to generate necessary nutrients in scant environments to promote survival. Apoptosis and autophagy are seemingly juxtaposed processes and it is often assumed that one inhibits the other, however, many studies suggest it is much more complicated than that1.
The two pathways share BH3-only proteins that play intricate roles during intrinsic apoptosis signaling on the mitochondrial membrane, but also play critical roles during the initiation step of autophagy. For example under basal conditions anti-apoptotic BH3 proteins (BCL-2, BCL-XL, MCL-1) inhibit pro-apoptotic family members (BID, BAX). These same anti-apoptotic proteins play an inhibitory role in the autophagy initiating BECN1 complex. Moreover, pro-apoptotic proteins including PUMA, NOXA and others, disrupt these inhibitory interactions in the BECN1 complex2. To add complexity, autophagy regulates the constitutive levels of the pro-apoptotic protein, PUMA: an example of how autophagy can protect cells from stimuli induced apoptosis3.
It is generally thought that once MOMP is initiated, the cells are committed to undergo apoptosis, however, recent studies have identified a small population of mitochondria that undergo MOMP without initiating the full signaling cascade resulting in death; a phenomenon known as incomplete MOMP. Cells with elevated autophagy can sustain incomplete MOMP while knockdown of core autophagy genes inhibits cell survival once MOMP has initiated. The level of autophagy within distinct cell populations can dictate the cellular response to different death receptor signaling, i.e. cells with high levels of autophagy are sensitive to FAS ligand induced apoptosis yet resistant to TRAIL induced apoptosis4. While these provide examples of how autophagy can regulate apoptosis, the converse is also true and apoptosis can directly affect autophagy. For example, there are two caspase-3 cleavage sites in BECN1, resulting in decreased autophagy and increased apoptosis5. ATG13 and AMBRA1, two other core autophagy genes, can also be substrates for caspase cleavage mediated by caspase-3 and caspase-8, respectively6,7. Although these two pathways have been intensely studied individually, the cross-play between the two is just now being illuminated, and the complex story that is unfolding is only the tip of the iceberg.
New Apoptosis Research Area Pages
