The capacity for limited turnover of cytoplasmic contents by autophagy or for the programmed death of specific cells plays an important role in development. However, the capacity to degrade cells and cellular contents necessitates strict regulatory safeguards to prevent indiscriminate destruction of essential components. Accordingly, macroautophagy is regulated through the action of kinases (e.g., Tor and Apg1), phosphatases (e.g., PP2A), and GTPases (Gαi3 and Ypt7) that dictate the conditions under which it operates and the targets of the sequestration process.
Autophagy involves dynamic rearrangements of cellular membranes. This is not surprising as this process can result in the engulfment of entire organelles. Some aspects of autophagy are similar to those of other subcellular trafficking events, for example, the targeting, docking, and fusion of the autophagosome requires components such as Rabs and SNARES that are used in both the secretory and endocytic transport systems. However, other components of the autophagy system are specific (see ). The origin of the sequestering membrane is not known, nor is it understood how this membrane can form an enwrapping vesicle in the cytosol. Formation of the autophagosome is topologically distinct from that of a transit vesicle that buds off a preexisting organelle and is likely to require a large number of gene products (), including those of a novel ubiquitinlike protein conjugation system (). The autophagic machinery is used for a range of processes that are carried out under different conditions and that display varying specificities.
The autophagic machinery is highly conserved in organisms as diverse as plants, animals, and yeast. Recent studies have demonstrated a role for autophagy in both promoting and preventing human diseases. In the last few years, tremendous advances have been made in identifying the molecular components required for macroautophagy through genetic studies in yeast. Combining these analyses with the pharmacological and biochemical information that is available from work in mammalian systems has begun to provide a detailed understanding of the mechanisms that underlie each stage of the autophagic process. Furthermore, workers in both plant and animal systems are exploiting the genomic data now available to identify homologs of the yeast APG genes for directed studies in these multicellular systems. Such studies should allow researchers to address tissue- and development-specific roles for autophagic degradation. Many questions still remain, including the following: What is the mechanism by which cells sense the starvation signal required to induce autophagy? What is the origin of the autophagosomal membrane? How does the autophagic machinery drive the deformation of membranes? How are specific substrates recognized as cargo for sequestration? However, with the progress that has been made in the last few years, it is likely that these and other important problems in the field of autophagy will be solved in the near future.