Lysosome sorting pathways

Study of Lysosomal Storage Diseases Revealed Key Components of the Lysosomal Sorting Pathway... 

Figure 8.4. Intracellular sorting pathways of RME. The initial binding and uptake steps [including receptor clustering in eoated or noncoated pits, internalization of the receptor-ligand complex into coated vesicles (noneoated in the ease of potoc3d osis), and fusion of vesicles to form endosomes] are common to all pathways. After entry into acidic endosomes, ligand and receptors are sorted and trafficked independently, whieh may result in degradation, recycling or transcytosis of either molecule (seetext). L, ligand R, receptor lysosomes are depicted as shaded circles. (Adaptedfrom Ref 10.)...

There have been many studies designed to establish whether the endosomal pathway to lysosomes, and the recycling of receptors is the same with clathrin-dependent and clathrin-independent pinocytosis. The pathway appears to be determined in the endosome, with perhaps the lysosome being the default pathway [54]. During this sorting process, some endosomes are transported to the Golgi apparatus and become associated with secretory vesicles. 

In a simplified view, the total flow is as follows (Fig. 8). Both soluble and membrane proteins that are translated at the membrane-bound ribosome are first localized at the ER. Some of them are transported to the Golgi apparatus, whereas others remain at the ER. At the Golgi apparatus, including the trans Golgi network (TGN), the next selection occurs some are transported to the plasma membrane, others to the endosome and to the lysosome/vacuole finally, and still others remain there. The lysosome is also an important organelle for the other transport system, the endocytic pathway. In this pathway, proteins at the plasma membrane are internalized by endocytosis. The sorting to lysosomes is treated in the next section. 

A nonubiquitous organelle, the melanosome, is specialized for melanin synthesis. It is somewhat similar to the lysosome, and the resident proteins are derived from the endocytic pathway. A sorting signal, the NQPLLT, was found in the cytoplasmic protein of a human membrane protein (Vijayasaradhi et al., 1995). 

Early endosomes are the main sorting station in the endocytic pathway. In their acidic interior (pH 5.9-6.0), the receptor and its ligand can be released. The receptor may be recycled to the surface by vesicles that fuse with the plasma membrane. Material that cannot escape from the early endosomes is further transported via multivesicular bodies to late endosomes and digesting lysosomes that contain a broad spectrum of peptidases and hydrolases in an acidic surrounding [for reviews on endocytosis see Refs. (10-12), for review on clathrin uptake see Refs. (9,13)]. 

FIGURE 27-35 Pathway taken by proteins destined for lysosomes, the plasma membrane, or secretion. Proteins are moved from the ER to the cis side of the Golgi complex in transport vesicles. Sorting occurs primarily in the trains side of the Golgi complex. 

Fig. 5.4 Endocytosis of GPCRs mediated by GRKs, arrestins and clathrin-coated pits. Receptor phosphorylation mediates recruitment of arrestins from the cytoplasm, the arres-tin interaction with other adaptotor proteins, and promotes receptor endocytosis by clathrin-coated pits. Internalised receptors may be sorted into a rapid recycling pathway, or to a degradative pathway into the lysosomes...

Figure 11.1 The intracellular trafficking pathway of plasmid DNA complexed by poly cationic lipid (lipoplex). Critical steps are indicated by numbers (1) endocytosis, sorting and recycling via vesicular compartments comprising the early (EE) and sorting endosomes (2) entrapment and degradation in the late-endosomes (LE) and lysosomes (3) destabilization of the endo-lysosomal membrane and release into the cytosol, (the precise location of this step is not known) (4) diffusion toward the nuclear pore complex (NPC) and degradation in the cytoplasm, and (5) nuclear translocation across the NPC.

The I-cell patient has proved invaluable for elucidation of the complex nature of intracellular packaging and sorting of lysosomal enzymes. The physiological importance of this signal-mediated pathway is evident in that fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy secrete rather than target most of their lysosomal enzymes. Thus, the molecular theme of I-cell disease is that of faulty lysosomal targeting, the inability to transport (i.e., sort) lysosomal enzymes from their site of synthesis to the lysosome. 

---