Abstract
Autophagy, a conserved catabolic process in eukaryotes, mediates the nutrient and energy homeostasis via the degradation of intracellular cytoplasmic materials and organelles by lysosomal machinery. It serves as a recycling mechanism for the rejuvenation of cell contents, which is known to be critical in various biological events, such as starvation response, neurodegeneration, immunity, inflammation, cancer and so on. Due to its complex nature, autophagy actually plays a dual role in relevant diseases. For example, as most anticancer drugs cause cellular stress, autophagy is often activated in cancer cells after drug treatment to promote cell survival under stress. Thus, both inducers and inhibitors of autophagy have been investigated for their potential therapeutic applications. Studies on the molecular mechanism of autophagy began with the identification of the autophagy-related (ATG) genes in yeast in the 1990s. So far, many protein factors have been found to participate in the formation of autophagosome. In particular, formation of the preautophagosomal structure (PAS) is essential for autophagy execution in yeast as well as mammals (Figure 1). Two ubiquitin-like protein conjugates are known to be involved in this process: Atg8–phosphatidylethanolamine (PE) and the Atg12–Atg5–Atg16 complex. Atg8–PE is equivalent to the LC3–phosphatidylethanolamine conjugate (LC3-II) in mammals. Atg8 was found to act as an important component of the scaffold during membrane expansion of PAS, and its amount in cell quantitatively relates to the PAS vesicle size. The Atg12–Atg5–Atg16 complex, which facilitates the lipidation of Atg8, is also believed to help direct Atg8–PE towards PAS. Mutations in the Atg12– Atg5–Atg16 complex lead to a decrease in Atg8–PE/LC3-II levels as well as a defective autophagosome. The studies mentioned above illustrate the importance of the Atg12–Atg5–Atg16 complex in autophagy. It is possible to develop effective autophagy inhibitors by targeting the protein–protein interactions (PPI) between Atg5–Atg16 and Atg5– Atg12. Atg12 is known to be covalently linked with Atg5 via a glycine residue at its C terminus. Mediated by the oligomerization of Atg16, the Atg12–Atg5 complex interacts noncova-
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