Overview of autophagy − Rakyat Biologi

The barrier function of the epidermis and of other epithelia depends on the maintenance of a pool of proliferating cells, cell differentiation, coordinated responses to various kinds of stress and the defense against infections. Among the subcellular processes involved in tissue homeostasis and defense, autophagy has been described in morphological studies for a long time. However, in recent years the molecular regulation of autophagy has become clearer and new research methods have facilitated the dissection of its functions in epithelia.

Autophagy is an evolutionarily conserved process in which the cell degrades its own components. It is critical for the intracellular quality control of proteins and the maintenance of metabolism during starvation and involved in development and differentiation as well as in anti-bacterial and anti-viral defense (1-3). Macroautophagy, microautophagy, and chaperone-mediated autophagy are different modes of autophagy, of which macroautophagy predominates in mammalian tissues (2, 4). In this review article the term “autophagy” will refer to macroautophagy.

More than thirty autophagy-related genes (Atg) control the process of autophagy. The functions of these genes and the mechanism of autophagy have been reviewed extensively (2, 5-7), and only some of the key features will be introduced here. Autophagy is initiated by the formation of a double membrane, most likely originating from the endoplasmic reticulum that encloses a part of the cytoplasm including protein complexes and organelles. This so-called autophagosome fuses with a lysosome so that the interior of the autophagosome is exposed to lysosomal enzymes that eventually degrade the cargo. One of the molecular reactions important for monitoring autophagy is the conjugation of Atg12 and Atg5 in a reaction that is mediated by Atg7 and Atg10. The Atg5-Atg12 conjugation system is essential for attaching LC3, the mammalian homolog of yeast Atg8, to the membrane of the autophagosome. The LC3 protein is produced as pro-LC3, a pro-protein which requires activation by the cysteine protease Atg4. Processing of pro-LC3 generates LC3-I, which is a cytoplasmic protein. During autophagy, LC3 becomes conjugated to phosphatidylethanolamine by the action of the enzymes Atg7 and Atg3 and localizes to the autophagosomal membrane. The lipidated form of LC3, named LC3-II, is present on the inner and the outer membrane of the autophagosome. When the autophagosome fuses with the lysosome, LC3 on the inner membrane is degraded by lysosomal proteases. LC3 on the outer membrane is de-lipidated by Atg4 and moves again to the cytosol (2, 5-7).

Autophagy contributes to cellular survival in situations of nutrient deprivation but also plays multiple roles in cells that are not starved, as will be described below. It is active in distinct cells of normal and diseased organs as well as in tumors (8). Parkinson’s, Alzheimer’s, Huntington’s disease, Crohn’s disease, type II diabetes, and many other diseases show aberrant levels of autophagy (2, 7, 9). Accordingly, the pharmacological modulation autophagy has been recognized as a potential therapeutic target in numerous diseases (10, 11).