ABSTRACT
Lysosomes are able to take up certain cytosolic proteins in a molecule-by-molecule fashion. This selective pathway of lysosomal proteolysis resembles in many respects the movement of proteins into the lumen of the endoplasmic reticulum (ER) and the import of proteins into mitochondria, chloroplasts, and peroxisomes.1'4 Redundant but biochemically related targeting peptides are components of all known substrate proteins for these targeting pathways. The substrate proteins bind to receptors in the organelle membranes, and then, with or without unfolding, are transported through a gated aqueous pore. Molecular chaperones outside and inside the organelle are required for separate steps in the import pathways.1'4
Background By the late 1960s it was clear that proteins had widely varying half-lives,5 some
examples of which are listed in Table 6.1. Such variability in degradation rates could not be easily explained based on electron microscopic images of entire mitochondria, for example, being engulfed by autophagic vacuoles and then digested by lysosomal cathepsins. Several investigators made innovative proposals about how proteins might selectively enter lysosomes by macroautophagy or microautophagy6 or how certain proteins might escape the digestion within lysosomes and reenter the cytosolic compartment.7 Certain aspects of these proposals still have merit.8,9
We began studying the enhanced protein degradation seen in tissues of diabetic and starved rats.10,11 In the liver of acutely diabetic rats the evidence was quite clear that the rate of protein degradation was increased.12 Early in starvation and after acute insulin withdrawal from rats made diabetic by injections of streptozotocin, degradation rates of most proteins were increased. This period also coincided with an increased number and size of macroautophagic vacuoles.13,14 At later times of starvation or insulin withdrawal, particular classes of proteins were degraded at enhanced rates but other classes were not.15 For example, small, basic, nonglycosylated proteins were degraded more rapidly, but large, acidic, glycoproteins were not, and this caused the small, basic, nonglycosylated proteins to be preferentially lost from the liver cytosol.16 Withdrawal of insulin from hepatocytes in cell culture also caused increased proteolysis, and this increase could be blocked by inhibitors of lysosomal proteolysis.17,18 Although other explanations regarding our results with diabetic rats were possible, the simplest explanation was that lysosomes could operate
in a selective fashion at later times of starvation and insulin withdrawal. We now know that this is true and have been fortunate to have made progress in understanding this selective lysosomal pathway of proteolysis.
