The first hypothesis for lysosomal biogenesis, formulated almost a half century ago, postulated that lysosomes arise as complete and functional organelles budding from the Golgi apparatus. These newly formed lysosomes were termed primary lysosomes in contrast to secondary lysosomes, which had already fused with incoming endosomes. However, the primary and secondary lysosome hypothesis has proved to have little validity as new research data allow a better understanding of the details of protein secretory pathways and the fate of endocytotic vesicles. It is now widely accepted that lysosomes are formed in a complex series of pathways that converge at the late endosomes, transforming them into lysosomes. These pathways are responsible for a targeted delivery of newly synthesized lysosomal enzymes and structural lysosomal membrane proteins into the late endosomes. As stated earlier, lysosomal enzymes are synthesized in the rER and sorted in the Golgi apparatus based on their binding ability to M-6-P receptors (see page 37).
Lysosomes have a unique membrane that is resistant to the hydrolytic digestion occurring in their lumen.
Lysosomes contain a collection of hydrolytic enzymes and are surrounded by a unique membrane that resists hydrolysis by their own enzymes (Fig. 2.19). The lysosomal membrane has an unusual phospholipid structure that contains cholesterol and a unique lipid called lysobisphosphatidic acid. Most of the structural lysosomal membrane proteins are classified into lysosome-associated membrane proteins (lamps), lysosomal membrane glycoproteins (lgps), and lysosomal integral membrane proteins (limps). The lamps, lgps, and limps represent more than 50% of the total membrane proteins in lysosomes and are highly glycosylated on the luminal surface. Sugar molecules cover almost the entire luminal surface of these proteins, thus protecting them from digestion by hydrolytic enzymes. Lysobisphosphatidic acids within the lysosomal membrane may play an important role in restricting the activity of hydrolytic enzymes directed against the membrane. The same family of membrane proteins is also detected in late
FIGURE 2.19 • Schematic diagram of a lysosome. This diagram shows a few selected lysosomal enzymes residing inside the lysosome and their respective substrates. The major lysosomal membrane-specifc proteins, as well as a few other proteins associated
H membrane impermeable to enzymes; contains specific lysosomal proteins, lamps, limps, and lgps with membrane transport, are also shown.
endosomes. In addition, lysosomes and late endosomes contain proton (H ) pumps that transport H ions into the lysosomal lumen, maintaining a low pH (4.7). The lysosomal membrane also contains transport proteins that transport the final products of digestion (amino acids, sugars, nucleotides) to the cytoplasm, where they are used in the synthetic processes of the cell or are exocytosed.
Certain drugs can affect lysosomal function. For example, chloroquine, an agent used in the treatment and prevention of malaria, is a lysosomotropic agent that accumulates in the lysosomes. It raises the pH of the lysosomal content, thereby inactivating many lysosomal enzymes. The action of chloroquine on lysosomes accounts for its antimalarial activity; the drug concentrates in the acidic food vacuole of the malaria parasite (Plasmodium falciparum) and interferes with its digestive processes, eventually killing the parasite.
Lysosomal membrane proteins are synthesized in the rER and have specific lysosomal targeting signal.