American Society for Microbiology

Autophagy in the eukaryotic cell

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The major cellular pathways for protein and organelle turnover are autophagy and proteasome-mediated degradation. These processes are important to maintain a well-controlled balance between anabolism and catabolism in order to have normal cell growth and development. They play an essential role during starvation, cellular differentiation, cell death, and aging but also in preventing some types of cancer (59). These degradation pathways permit the cell to eliminate unwanted or unnecessary organelles and to recycle the components for reuse (54, 59).

The lysosome or vacuole is the major catabolic factory in eukaryotic cells and contains a range of hydrolases capable of degrading all cellular constituents. Organelle turnover is accomplished exclusively at this location through a process of autophagy that is conserved among yeast, plant, and animal cells. Microautophagy involves the uptake of cytoplasm at the lysosome or vacuole surface but has not been well characterized. In contrast, degradation by macroautophagy involves membrane engulfment at an initial site that is separate from this organelle. In mammalian cells, this process has been known for a long time, but the early studies were primarily phenomenological. Molecular components have been identified in the last decade by genetic screening of the yeast Saccharomyces cerevisiae (32, 80, 117, 121) and in recent years by two-hybrid screening of the same organism with predetermined baits or by genome-wide approaches (20, 42, 45, 71, 123). Surprisingly, molecular genetic studies with yeast have shown the overlap of the macroautophagy machinery with that used for peroxisome degradation (pexophagy) and the cytoplasm-to-vacuole targeting (Cvt) pathway (31, 39, 99), which ensures the delivery of the resident vacuolar protease aminopeptidase I (Ape1) (58, 97). These processes operate under different nutritional conditions, and the Cvt pathway in particular is biosynthetic. However, biochemical and morphological analyses have shown that the basic mechanism in all three processes is the sequestration of the cargo material (precursor Ape1 [prApe1], bulk cytoplasm, or specific organelle) within double-membrane structures (5-7, 39, 113).

The biogenesis and consumption of these vesicles can be divided into four discrete steps: induction and cargo packaging, formation and completion, docking and fusion, and breakdown. Figure 1 shows schematically these events for macroautophagy, the Cvt pathway, and pexophagy. The induction of vesicle formation during macroautophagy is stimulated by cellular signals such as starvation (113), whereas during Cvt transport the binding of prApe1 to its receptor may be the signal that triggers induction (98). Upon completion, the sequestering vesicle (called an autophagosome or Cvt vesicle, respectively) docks with the lysosome or vacuole and then fuses with it. In this way, the inner vesicle is liberated inside the lysosome or vacuole, where it is finally consumed by hydrolases. In addition to induction, another major difference between these pathways appears to be the regulation of the size of the vesicle. Autophagosomes that form during starvation have anywhere from 8- to 200-fold more volume than Cvt vesicles that are induced under nutrient-rich conditions (300 to 900 nm versus 140 to 160 nm in diameter, respectively) (6). Finally, several lines of evidence suggest that the source of the sequestering vesicles for macroautophagy and the Cvt pathway differ at least in part. For example, macroautophagy but not the Cvt pathway requires the Sec12, Sec16, Sec23, and Sec24 proteins for formation of the membrane coat, COPII, that drives the formation of vesicles from the endoplasmic reticulum (41). Conversely, only the Cvt pathway utilizes the tSNARE protein Tlg2 and the Sec1 homologue Vps45 (1).

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