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Macroautophagy is a dynamic process involving the rearrangement of subcellular membranes to sequester cytoplasm and organelles for delivery to the lysosome or vacuole where the sequestered cargo is degraded and recycled. This process takes place in all eukaryotic cells. It is highly regulated through the action of various kinases, phosphatases, and guanosine triphosphatases (GTPases). The core protein machinery that is necessary to drive formation and consumption of intermediates in the macroautophagy pathway includes a ubiquitin-like protein conjugation system and a protein complex that directs membrane docking and fusion at the lysosome or vacuole. Macroautophagy plays an important role in developmental processes, human disease, and cellular response to nutrient deprivation.
Normal cell growth and development requires a well-controlled balance between protein synthesis and organelle biogenesis versus protein degradation and organelle turnover. The major pathways for degradation of cellular constituents are autophagy and cytosolic turnover by the proteasome. These degradative pathways are particularly important during development and under certain environmental stress conditions. For example, cellular death and resorption are critical during processes that involve extensive cellular remodeling such as insect metamorphosis, postpartum luteal cell regression, differentiation, and aging (1, 2), as well as in preventing various disease states including cardiomyopathy and some types of cancer. In some cases, degradation and turnover of the entire cell occurs as part of programmed cell death. At other times, turnover occurs on a subcellular scale; under starvation conditions, cells need to scavenge nonessential proteins and organelles and to recycle the components for reuse in the cytosol.
In eukaryotic cells, the lysosome or vacuole is a major degradative organelle. This compartment contains a range of hydrolases that are able to degrade essentially any subcellular constituent (proteins, lipids, nucleic acids, and carbohydrates). In addition, regulated turnover of organelles is confined to the lysosome. Cytoplasmic components are degraded within the lysosome by microautophagy, chaperone-mediated autophagy, and macroautophagy (3-5). In mammalian cells, microautophagy has not been well characterized, and chaperone-mediated autophagy is a secondary response that temporally follows macroautophagy. In this review, we will limit our discussion to macroautophagy, the major inducible pathway for general turnover of cytoplasmic components. The process of macroautophagy is seen in all nucleate cell types that have been analyzed. The morphology of the process is essentially the same in...