Mannose Phosphate-Independent Membrane Association of Lysosomal Enzymes Occurs After Passage of the Golgi Complex

Abstract

The degradative action of lysosomes depends primarily on the hydrolytic enzymes present within their lumen. However, the number of lysosomes per cell and their level of activity is regulated by events controlled by constituents of their limiting membrane. Therefore, study of formation of new lysosomes, the composition of lysosomal membranes and their maintenance is the basis for understanding the biology of lysosomes. Much is known about the biosynthesis, sorting and turnover of soluble lysosomal enzymes (Von Figura and Hasilik, 1986; Kornfeld and Mellman, 1989). They are targeted through endosomes to lysosomes via the mannose phosphate receptor (MPR). In the endosomes MPR separates from the ligand (the soluble lysosomal enzyme) and returns to the Golgi complex or the cell surface, while the enzyme is transported to the lysosomes. Other mechanisms to direct proteins to the lysosomes must exist (Neufeld and McKusik, 1983). The glycoproteins of the limiting lysosomal membrane have no mannose 6-phosphate and yet are very efficiently transported to the lysosomes. In addition, some enzymes such as glucocerebrosidase (deficient in Gaucher disease) and acid phosphatase have their own unique pathways to reach the lysosomes (Erickson, et al., 1985; Braun et al., 1989). We We have studied the intracellular transport between the Golgi complex and the lysosomes of two lysosomal glycoproteins cathepsin D, a MPR-dependent soluble enzyme and glucocerebrosidase, a MPR-independent enzyme after their synthesis in the rough endoplasmic reticulum (RER).