Figure 216

Schematic diagram of endosomal compartments of the cell. This diagram shows the fate of protein (red circles) endocytosed from the cell surface and destined for lysosomal destruction. Proteins are first found in endocytotic (coated) vesicles that deliver them to early endosomes, which are located in the peripheral part of cytoplasm. Because of the sorting capability of the early endosomes, receptors are usually recycled to the plasma membrane, and endocytosed proteins are transported via multivesicular bodies (MVB) to late endosomes positioned near the Golgi apparatus and the nucleus. The proteins transported to late endosomes eventually will be degraded in lysosomes. Note the acidification scale (left) that illustrates changes of pH from early endosomes to lysosomes. The acidification is accomplished by the active transport of protons into endosomal compartments.

slightly more acidic environment (pH 6.2 to 6.5) than the cytoplasm of the cell. In contrast, late endosomes have a more complex structure and often exhibit onion-like internal membranes. Their pH is more acidic, averaging 5.5. TEM studies reveal specific vesicles that transport substances between early and late endosomes. These vesicles, called multivesicular bodies (MVB), are highly selective transporters. Within early endosomes, proteins destined to be transported to late endosomes are sorted and separated from proteins destined for recycling and packaging into MVBs (Fig. 2.16). In general, substances transported to late endosomes are eventually degraded in lysosomes in a default process that does not require any additional signals. For that reason, late endosomes are also called prelysosomes.

The major function of early endosomes is to sort and recycle proteins internalized by endocytotic pathways

Early endosomes sort proteins that have been internalized by endocytotic processes. The morphologic shape and geometry of the tubules and vesicles emerging from the early endosome create an environment in which localized changes in pH constitute the basis of the sorting mechanism. This mechanism includes dissociation of lig-ands from their receptor protein; thus, in the past, early endosomes were referred to as compartments of uncoupling receptors and ligands (CURLs). In addition, the narrow diameter of the tubules and vesicles may also aid in the sorting of large molecules, which can be mechanically prevented from entering specific sorting compartments. After sorting, most of the protein is rapidly recycled, and the excess membrane is returned to the plasma membrane.

The fate of the internalized ligand-receptor complex depends on the sorting and recycling ability of the early endosome

The following pathways for processing internalized ligand-receptor complexes are present in the cell:

• The receptor is recycled and the ligand is degraded. Surface receptors allow the cell to bring in substances selectively through the process of endocytosis. This pathway occurs most often in the cell; it is important because it allows surface receptors to be recycled. Most ligand-receptor complexes dissociate in the acidic pH of the early endosome. The receptor, most likely an integral membrane protein (see page 22), is recycled to the surface via vesicles that bud off the ends of narrow-diameter tubules of the early endosome. Ligands are usually sequestered in the spherical vacuolar part of the endosome that will later form MVBs, which will transport the ligand to late endosomes for further degradation in the lysosome (Fig. 2.17a). This pathway is described for the low-density lipoprotein (LDL)-receptor coated vesicle

LDL receptor coated vesicle

LDL receptor

lysosome transferrin transferrin receptor Fe

lysosome late endosome 3 b early endosome FIGURE 2.17

Fate of receptor and ligand in receptor-mediated endocytosis. This diagram shows four major pathways along which the fate of internalized ligand-receptor complexes is determined, a. The internalized ligand-receptor complex dissociates, the receptor is recycled to the cell surface, and the ligand is directed to late endosomes and eventually degraded within lysosomes. This processing pathway is used by the LDL/LDL-receptor complex, insulin-GLUT receptor complex, and a variety of peptide hormone-receptor complexes, b. Both internalized receptor and ligand are recycled. Ligand-receptor complex dissociation does not occur, and the entire complex is recycled to the surface. An example is the iron-transferhn/transferrin-receptor complex that uses this processing pathway. Once iron is released in the

EG F receptor

secretory component oflgA X *

IgA receptor

endosome, the transferrin-receptor complex returns to the cell surface, where transferrin is released, c. The internalized ligand-receptor complex dissociates in the early endosome. The free ligand and the receptor are directed to the late endosomal compartment for further degradation. This pathway is used by many growth factors (i.e., epidermal growth factor (EGF)/EGF-receptor.) d. The internalized ligand-receptor complex is transported through the cell. Dissociation does not occur, and the entire complex undergoes transcytosis and release at a different site of the cell surface. This pathway is used during secretion of immunoglobulins (secretory IgA) into saliva. The antibody IgA-receptor complex is internalized at the basal surface of the secretory cells in the salivary gland and released at the apical surface.

complex, insulin-glucose transporter (GLUT) receptor complex, and a variety of peptide hormones and their receptors.

• Both receptor and ligand are recycled. Ligand-receptor complex dissociation does not always accompany receptor recycling. For example, the low pH of the endosome dissociates iron from the iron-carrier protein transferrin, but transferrin remains associated with its receptor. Once the transferrin-receptor complex returns to the cell surface, however, transferrin is released. At neutral extracellular pH, transferrin must again bind iron to be recognized by and bound to its receptor. A similar pathway is recognized for major histocompatibility complex (MHC) I and II molecules, which are recycled to the cell surface with a foreign antigen protein attached to them (Fig. 2.17b).

• Both receptor and ligand are degraded. This pathway has been identified for epidermal growth factor (EGF) and its receptor. Like many other proteins, EGF binds to its receptor on the cell surface. The complex is internalized and carried to the early endosomes. Here, EGF dissociates from its receptor, and both are sorted, packaged in separate MVBs, and transferred to the late endosome. From there, both ligand and receptor are transferred to lysosomes, where they are degraded (Fig. 2.17c).

• Both receptor and ligand are transported through the cell. This pathway is used for secretion of immunoglobulins (secretory IgA) into saliva or secretion of maternal IgG into milk. During this process, commonly referred as transcytosis, substances can be altered as they are transported across the epithelial cell (Fig. 2.17d).


Lysosomes are digestive organelles that were recognized only after histochemical procedures were used to demonstrate lysosomal enzymes

Lysosomes are organelles rich in hydrolytic enzymes such as proteases, nucleases, glycosidases, lipases, and phospholipases. They are responsible for degradation of macromolecules derived from endocytotic pathways as well as from the cell itself in a process known as au-tophagy (removal of cytoplasmic components, particularly membrane-bounded organelles, by digesting them within lysosomes).

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.

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. 2.18). Most of the structural lysosomal membrane proteins are classified into lysosome-associatecl membrane proteins (lamps), lipids

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