Autophagy.

Autophagy or autophagocytosis are terms given to a membrane-mediated process in eukaryotic cells in which portions of cytoplasm are sequestered within vacuoles and degraded by acid hydrolases that are acquired by fusion with lysosomes. Although vacuoles of this type may be formed under pathologic conditions, autophagy is fundamentally a physiologic process which plays indispensible roles in cell restructuring and in the ongoing turnover of cytoplasmic macromolecules. Sequestration is the one step in this pathway that separates autophagy from other degradative processes in the cell. As a volume uptake mechanism it is relatively nonselective (one exception is discussed insection 3.1.2.) and, accordingly, will sequester most organelles and macromolecules in proportion to their cytoplasmic abundance. Moreover, it permits the simultaneous handling of more than one class of macromolecule. This is illustrated in the perfused rat liver by the striking similarity in the accelerated responses of protein and RNA degradation to amino acid deprivation (see Table I). Although the appearance of the vacuoles varies widely among cells, it is, nevertheless, highly conserved and found in nearly all lower plants and animals as well as in higher species. In yeast, for example, a vacuole that expresses autophagic function (Takeshige et al., 1992; reviewed by Jones and Murdock, 1994) plays a major role in the supply of endogenous amino acids. A similar role for the vacuole is found in germinating seeds (Nishimura and Beevers, 1979) and in the turnover of intracellular proteins in protoplasts of cultured plant cells (Canut et al., 1985). An interesting variant of autophagy is utilized in cell remodeling where irreversible alterations are involved (Marty, 1978; Paavola, 1978 a,b), and an enzymatically unique type degrades intracellular membranes in the amoeba Tetrahymena pyriformis to provide lipid substrate for gluconeogenesis by the glyoxalate pathway (May et al., 1982). Finally, in the mammalian heptocyte, where both protein turnover and the need for endogenous amino acids are large, autophagy is highly expressed and closely regulated by complex amino acid feedback and hormonal mechanisms (reviewed by Mortimore and Pösö, 1987). Taken together, these findings attest to a fundamental role of autophagy in cellular homeostasis. In this chapter the authors will discuss the main features of general intracellular protein and RNA degradation and the major classes of autophagy and present a current overview of autophagic regulation and its mechanism, focusing primarily on the mammalian hepatocyte which has been extensively studied as a model for the pathway.