Apoptosis and autophagy: regulatory connections between two supposedly different processes

Abstract

Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes.

Figure 1. Schematic of macroautophagy

A membrane forms and expands to sequester cytoplasm and organelles in a double-membrane autophagosome. The initial step requires the activity of a Type III PI3kinase and the Beclin1 protein and is regulated by diverse signaling pathways providing both positive and negative signals. Completion and expansion of the autophagosome requires the products of two protein conjugation systems that produce Atg5-Atg12 and Atg8/LC3-PE. The mature autophagosome fuses with a lysosome through a step that requires the Rab7 GTPase and the LAMP2 protein to produce the autophagolysosome in which the contents are degraded.

Figure 2. Regulation of apoptosis and autophagy by Bcl-2 and Bcl-xL

Bcl-2 (and Bcl-xL) inhibits apoptosis by blocking activation of Bax (and Bak) to prevent MOMP and subsequent release of cytochrome c and other apoptogenic proteins from the mitochondria. Alternatively, Bcl-2 at the endoplasmic reticulum can inhibit autophagy by interacting with the Beclin 1 BH3 domain and by preventing calcium release from the ER to block the activation of a signaling pathway involving CAMKK-ß, AMPK which represses mTOR to activate autophagy.

Figure 3. Regulation of apoptosis by Atg 5

The autophagy regulator Atg 5 induces caspase activation by interacting with the adaptor protein FADD, a component of the extrinsic apoptosis pathway. Alternatively, cleavage of Atg 5 by calpain causes the truncated Atg 5 protein to translocate to the mitochondria to induce MOMP resulting in cytochrome c release and caspase activation.

Figure 4. Cell death continuum

Mechanistic interactions between regulators of apoptosis autophagy and necrosis control whether a cell lives or dies and determine the particular facets of the death mechanism with characteristics of apoptosis, necrosis etc. that occur in the dying cells. Perturbation of these interactions may alter the amount and characteristics of cell death.