Regulation and function of autophagy during cell survival and cell death

Abstract

Autophagy is an important catabolic process that delivers cytoplasmic material to the lysosome for degradation. Autophagy promotes cell survival by elimination of damaged organelles and proteins aggregates, as well as by facilitating bioenergetic homeostasis. Although autophagy has been considered a cell survival mechanism, recent studies have shown that autophagy can promote cell death. The core mechanisms that control autophagy are conserved between yeast and humans, but animals also possess genes that regulate autophagy that are not present in yeast. These regulatory differences may be explained by the need to control autophagy in a cell context-specific manner in multicellular animals, such as during cell survival and cell death. Autophagy was thought to be a bulk cytoplasmic degradation mechanism, but recent studies have shown that specific cargo is recruited for degradation. This suggests the possibility that either cell survival or death may be regulated by selective autophagic clearance of cytoplasmic material. Here we summarize the mechanisms that regulate autophagy and how they may contribute to cell survival and death.

Figure 1.

Macroautophagy (autophagy) delivers cytoplasmic cargo to lysosomes for degradation, and involves membrane formation and fusion. The isolation membrane is initiated from a membrane source known as the from the phagophore assembly site (PAS). The isolation membrane surrounds cargo, including organelles and proteins, to form a double membrane autophagosome. Autophagosomes fuse with lysosomes to form autolysosomes in which the cargo is degraded by lysosomal hydrolases.

Figure 2.

Core pathways that regulate autophagy. Atg1 and its interacting proteins, Vps34 and its interacting proteins, and two ubiquitin-like conjugation systems are required for the elongation of the isolation membrane and formation of an autophagosome.

Figure 3.

AMPK and mTOR are conserved kinases that sense energy and nutrient stress, and influence the activity of Atg1 to regulate autophagy. mTOR influences the activity of the Atg1 complex and autophagy. AMPK regulates autophagy by inhibition of mTOR by phosphorylation of TSC2 and Raptor. AMPK can also influence autophagy by phosphorylation of Atg1/Ulk1.

Figure 4.

The relationship between autophagy and caspases is cell context specific during cell death. (A) During cell death of Drosophila larval salivary glands, autophagy and caspases function in parallel genetic pathways. (B) Autophagy degrades the inhibitor of apoptosis (IAP) protein Bruce enabling caspase activation during fly cell death in oogenesis. By contrast, starvation-induced autophagy leads to degeneration of egg chambers during oogenesis, and the caspase DCP-1 and IAP protein Bruce are required for autophagy to occur in this context. These studies indicate that autophagy and caspases function in an epistatic regulatory hierarchy. (C) Autophagy is essential for cell death during fly midgut cell death, while caspases do not appear to play a significant role in the elimination of this tissue.