Lysosomal enzyme trafficking: from molecular mechanisms to human diseases.

Lysosomes degrade and recycle macromolecules that are delivered through the biosynthetic, endocytic, and autophagic routes. Hydrolysis of the different classes of macromolecules is catalyzed by about 70 soluble enzymes that are transported from the Golgi apparatus to lysosomes in a mannose 6-phosphate (M6P)-dependent process. The molecular machinery that generates M6P tags for receptor-mediated targeting of lysosomal enzymes was thought to be understood in detail. However, recent studies on the M6P pathway have identified a previously uncharacterized core component, yielded structural insights in known components, and uncovered functions in various human diseases. Here we review molecular mechanisms of lysosomal enzyme trafficking and discuss its relevance for rare lysosomal disorders, cancer, and viral infection. The degradative functions of lysosomes depend on modification of ~70 hydrolases with the lysosomal targeting signal mannose 6-phosphate (M6P). In the Golgi, the site-1-protease-activated GlcNAc-1-phosphotransferase (GNPT) complex catalyzes the formation of M6P tags to allow sorting of lysosomal enzymes by M6P receptors. The lysosomal enzyme trafficking factor (LYSET) stabilizes and retains the GNPT complex in the Golgi. The loss of LYSET causes a severe inherited fatal disease with skeletal and mental abnormalities related to the lysosomal storage disorder mucolipidosis II. The M6P pathway is critical for lysosomal turnover of endosomal and autophagic cargoes, lysosomal nutrient acquisition in cancer, and infection of pathogenic, cathepsin-dependent viruses. [ABSTRACT FROM AUTHOR]