I-cell disease is due to a single gene defect and, like most genetic enzyme deficiencies, it is recessive—that is, it occurs only in individuals having two copies of the defective gene. In patients with I-cell disease, all the hydrolases missing from lysosomes are found in the blood: because they fail to sort properly in the Golgi apparatus, they are secreted rather than transported to lysosomes. The mis-sorting has been traced to a defective or missing GlcNAc phosphotransferase. Because lysosomal enzymes are not phosphorylated in the cis Golgi network, the M6P receptors do not segregate them into the appropriate transport vesicles in the TGN. Instead, the lysosomal hydrolases are carried to the cell surface and secreted.
In I-cell disease, the lysosomes in some cell types, such as hepatocytes, contain a normal complement of lysosomal enzymes, implying that there is another
Figure 13–45 The transport of newly synthesized lysosomal hydrolases to endosomes. The sequential action of two enzymes in the cis and trans golgi network adds mannose 6-phosphate (M6p) groups to the precursors of lysosomal enzymes (see figure 13–46). The M6p-tagged hydrolases then segregate from all other types of proteins in the Tgn because adaptor proteins (not shown) in the clathrin coat bind the M6p receptors, which, in turn, bind the M6p-modified lysosomal hydrolases. The clathrin-coated vesicles bud off from the Tgn, shed their coat, and fuse with early endosomes. at the lower ph of the endosome, the hydrolases dissociate from the M6p receptors, and the empty receptors are retrieved in retromercoated vesicles to the Tgn for further rounds of transport. In the endosomes, the phosphate is removed from the M6p attached to the hydrolases, which may further ensure that the hydrolases do not return to the Tgn with the receptor.
with GlcNAc attached to mannose in oligosaccharide pathway for directing hydrolases to lysosomes that is used by some cell types but not others. Alternative sorting receptors function in these M6P-independent pathways. Similarly, an M6P-independent pathway in all cells sorts the membrane proteins of lysosomes from the TGN for transport to late endosomes, and those proteins are therefore normal in I-cell disease.
Targeting of material to lysosomes is not necessarily the end of the pathway. Lysosomal secretion of undigested content enables all cells to eliminate indigestible debris. For most cells, this seems to be a minor pathway, used only when the cells are stressed. Some cell types, however, contain specialized lysosomes that have acquired the necessary machinery for fusion with the plasma membrane. Melanocytes in the skin, for example, produce and store pigments in their lysosomes. These pigment-containing melanosomes release their pigment into the extracellular space of the epidermis by exocytosis. The pigment is then taken up by keratinocytes, leading to normal skin pigmentation. In some genetic disorders, defects in melanosome exocytosis block this transfer process, leading to forms of hypopigmentation (albinism). Under certain conditions, multivesicular bodies can also fuse with the plasma membrane. If that occurs, their intralumenal vesicles are released from cells. Circulating small vesicles, also called exosomes, have been observed in the blood and may be used to transport components between cells, although the importance of such a mechanism of potential communication between distant cells is unknown. Some exosomes may derive from direct vesicle budding events at the plasma membrane, which is a topologically equivalent process (see Figure 13–57).