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6 Heat Shock 70-kD Proteins and Lysosomal Proteolysis

J. Fred Dice, Fernando Agarraberes, Melissa Kirven-Brooks, Laura J. Terlecky, Stanley R. Terlecky


There are multiple pathways of intracellular proteolysis in eukaryotic cells (Dice 1987; Hershko and Ciechanover 1992; Olson et al. 1992). The best studied cytosolic pathway is dependent on ATP and ubiquitin and is responsible for the degradation of many abnormal proteins as well as many short-lived normal proteins (Rechsteiner 1991; Hershko and Ciechanover 1992). Other cytosolic proteolytic pathways are independent of ubiquitin, and still others are not cytosolic but are contained within organelles such as the endoplasmic reticulum and mitochondrion (Olson et al. 1992).

It is also well established that lysosomes have an important role in overall proteolysis (Mortimore 1987), and lysosomes appear to be able to internalize intracellular proteins in a variety of ways. For example, degradation of many plasma membrane proteins, as well as certain other intracellular membrane proteins, is through endocytosis and delivery to lysosomes (Fig. 1) (Hare 1990). In well-nourished cells, lysosomes appear to be able to internalize cytosolic proteins by a poorly understood process called microautophagy (Fig. 1) in which the lysosomal membrane invaginates at multiple locations (Ahlberg et al. 1982; Dice 1987).

These intralysosomal vesicles presumably decompose, whereupon their contents can be digested by lysosomal hydrolases. When cultured cells reach confluence and in certain tissues of fasted animals, macroautophagy (Fig. 1) is stimulated (Cockle and Dean 1982; Knecht et al. 1984; Mortimore 1987). Macroautophagy begins with the formation of double-membraned autophagic vacuoles that sequester areas of cytoplasm. The membranes of these autophagic vacuoles are derived from ribosome-free areas of the rough endoplasmic...

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