This specifically targets lysosomal enzymes because they all have specific protein recognition sequences that the phosphotransferase binds to before transferring the P-GlcNAc.
Although the lysosomal enzymes are tagged in the cis Golgi, they do not sort until the trans Golgi, when mannoseP receptors bind to the lysosomal enzymes and form lysosomal vesicles that will bud off and travel to late endosomes and lysosomes to deliver their acid hydrolase payload. Again, the pH change is important: in the somewhat acidic pH 6. When one or more acid hydrolases do not function properly or do not make it into the lysosome due to improper sorting, the result is incomplete digestion of the lysosomal contents.
This in turn leads to the formation of large inclusions of partially digested material inside the lysosomes. This accumulation of material can be cytotoxic, and genetic disorders that affect the expression or sorting of lysosomal hydrolases are collectively referred to as lysosomal storage diseases.
These fall into several categories depending on the types of molecules accumulated. Many lysosomal storage diseases have similar presentation: developmental abnormalities, especially stunted bone growth, lack of fine facial features, and neuromuscular weakness.
Since it depends greatly on the contents of the endosome s that fused with it, the size and contents of lysosomes can vary greatly. In fact, the lysosome may also degrade internal cellular components through the process of autophagy. Usually, this is initiated under starvation conditions which lead to inhibition of mTor, and subsequent expression of autophagic genes.
These then interact with mitochondria and other cellular components, and promote the formation of a double-membraned autophagosome around them. The origin of the membranes is unclear, although the ER is suspected.
Finally, the autophagosome fuses with a lysosome, and the acid hydrolases break down the cell parts for energy. A variation on this called microautophagy can also occur, in which the lysosome itself invaginates a bit of cytoplasmic material and internalizes an intralysosomal vesicle that is then broken down. The most severe, I-cell disease mucolipidosis type II occurs when nearly all lysosomal enzymes are missing in the fibroblasts of the affected individual.
There is severe developmental delay and early growth failure, neuromuscular problems, and malformations in early skeletal development. The severity of this disorder is due to the almost complete lack of lysosomal enzymes, which is caused by a deficiency of GlcNAc phosphotransferase. Punctate red spots are visible where labeled transferrin was internalized. Specific receptor-mediated endocytosis pathways can be investigated with a variety of fluorescent ligands targeted to common receptors, including, EGF, LDL, and transferrin.
Assays require a wash step to remove unbound conjugates from the cell surface or quenching of the extracellular signal. Visualization of transferrin and transferrin receptors in A cells. A cells incubated with green-fluorescent Alexa Fluor transferrin , then fixed and permeabilized.
Transferrin receptors were identified with anti—transferrin receptor, mouse IgG1 monoclonal antibody and visualized with red-fluorescent Alexa Fluor goat anti—mouse IgG antibody. Yellow fluorescence indicates regions of co-localization. Nuclei were stained with DAPI.
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