Autophagy and apoptosis: what is the connection?

Abstract

The therapeutic potential of autophagy for the treatment cancer and other diseases is beset by paradoxes stemming from the complexity of the interactions between the apoptotic and autophagic machinery. The simplest question of how autophagy acts as both a protector and executioner of cell death remains the subject of substantial controversy. Elucidating the molecular interactions between the processes will help us understand how autophagy can modulate cell death, whether autophagy is truly a cell death mechanism, and how these functions are regulated. We suggest that, despite many connections between autophagy and apoptosis, a strong causal relationship wherein one process controls the other, has not been demonstrated adequately. Knowing when and how to modulate autophagy therapeutically depends on understanding these connections.

Figure 1. Macroautophagy

The autophagic process degrades cellular macromolecules and organelles releasing metabolites to provide the cell with energy and anabolic building blocks to aid in survival and repair during nutrient deprivation or cellular damage. The Ubiquitin-like conjugation cascade leads to the lipidation of LC3 and conjugation of Atg5-Atg12, two key elements in the formation of the phagophore. The autophagic process begins (autophagy induction) with formation of the phagophore, its elongation and closure to form the autophagosome that then fuses with lysosomes resulting in degradation of the contents (autophagic flux).

Figure 2. Apoptosis

Key proteins involved in the intrinsic and extrinsic apoptotic pathways are depicted focusing on the components with known links to autophagy mentioned in the text. The extrinsic pathway results from the binding of extracellular death ligands which transduce a signal resulting in the formation of the death inducing signaling complex and activation of caspase-8. This activation is potentiated by p62-mediated aggregation leading to efficient activation of caspase-8. Caspase-8 then activates mitochondrial outer membrane permeabilization through the formation of Bax/Bad/Bak pores leading to cytoplasmic Cytochrome-C, that activates the apoptosome and effector caspases (Caspase-3), and the release of SMAC (Diablo), a protein that disables Inhibitor of Apoptosis Proteins (IAPs). Activated effector (executioner) caspases then cleave multiple targets resulting in cell death.

Figure 3. Linking Autophagy and Apoptosis

Connections between the autophagic and apoptotic processes. a. Atg5 activates DISC via an interaction with FADD. b. FLIP inhibits Atg3-LC3 association and therefore induction of autophagy. c. Atg12-Atg3 conjugation inhibits mitochondrial fission and apoptosis, independent of autophagy. d. p62 promotes aggregation and activation of Caspase-8 which, paradoxically, is degraded by autophagy, likely through its interaction with p62. e. Dap kinase phosphorylation of Beclin-1 promotes autophagy. f. Bcl-2 interaction with Beclin-1 inhibits autophagy. g. p53 can both promote and inhibit autophagy depending on the context. h. Autophagic cell death. Well established links are depicted with solid lines and less established links are shown with dashes. More information about each interaction is contained in Text Box 1 and the references therein, or in the text.