Some endosomes also communicate with the vesicular transport system of the rER. This pathway provides constant delivery of newly synthesized lysosomal enzymes, or hydrolases. A hydrolase is synthesized in the rER as an enzymatically inactive precursor called a prohydrolase. This heavily glycosylated protein then folds in a specific way so that a signal patch is formed and exposed on its surface. This recognition signal is created when specific amino acids are brought into close proximity by the three-dimensional folding of the protein. The signal patch on a protein destined for a lysosome is then modified by several enzymes that attach mannose-6phosphate (M-6-P) to the prohydrolase surface. M-6-P acts as a target for proteins possessing an M-6-P receptor. M-6-P receptors are present in early and late endosomes, lysosomes, and the Golgi apparatus, which is involved in sorting and retrieving secreted prohydrolases destined for transport to endosomes (Fig. 2.16). The acidic environment of late endosomes causes the release of prohydrolases from the M-6-P receptors. Prohydrolases are next activated by  cleavage and by removing phosphate groups from the  mannose residues.
Early and late endosomes differ in their cellular localization, morphology, and state of acidification and function.
Early and late endosomes are localized in different areas of the cell. Early endosomes can be found in the more  peripheral cytoplasm, whereas late endosomes are often positioned near
FIGURE 2.16 • Pathways for delivery of newly synthesized lysosomal enzymes. Lysosomal enzymes (such as lysosomal hydrolases) are synthesized and glycosylated within the rough endoplasmic reticulum (rER). The enzymes then fold in a specifc way so that a signal patch is formed, which allows for further modifcation by the addition of M-6-P, which allows the enzyme to be targeted to specifc proteins that possess M-6-P receptor activity. M-6-P receptors are present in the TGN of the Golgi apparatus, where the lysosomal enzymes are sorted and packaged into vesicles later transported to the early or late endosomes.
the Golgi apparatus and the nucleus. An early endosome has a tubulovesicular structure: The lumen is subdivided into cisternae that are separated by invagination of its membrane. It exhibits only a 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 onionlike 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 (MVBs), 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. 2.17). In general, substances transported to late endosomes are eventually degraded in lysosomes in a default process that does not require any additional signals. Because late endosomes mature into lysosomes, they are also called prelysosomes. Advances in videomicroscopy now allow researchers to  observe the complex behavior of these organelles; late lysosomes may fuse with each other or with mature lysosomes.
The major function of early endosomes is to sort and recycle proteins internalized by endocytotic pathways.
MVBHpH 6.2 pH 5.5 pH 4.7