Lysosomes endocytosis

Vesicles transport extracellular particles and membrane-proteins into the cell, where they fuse with the lysosomes (endocytosis, see Chapter 5). 

Mucolipin, also known as mucolipin 1 or mucolipidin (encoded by the MCOLN1 gene), is a TRP channel-related membrane protein, most probably residing in intracellular membranes. Is defective in mucolipidosis type IV disease, a developmental neurodegenerative disorder characterized by lysosomal storage disorder and abnormal endocytosis of lipids. The fimction of mucolipin is unknown. 

LDL (apo B-lOO, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-lOO binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits in a coordinated manner HMG-CoA synthase, HMG-CoA reductase, and, therefore, cholesterol synthesis stimulates ACAT activ-... 

There are receptors (TfRs) on the surfaces of many cells for transferrin, it binds to these receptors and is internalized by receptor-mediated endocytosis (compare the fate of LDL Chapter 25). The acid pH inside the lysosome causes the iron to dissociate from the protein. The dissociated iron leaves the endosome via DMTl to enter the cytoplasm. Unlike the protein component of LDL, apoTf is not degraded within the lysosome. Instead, it remains associated with its receptor, returns to the plasma membrane, dissociates from its receptor, reenters the plasma, picks up more iron, and again delivers the iron to needy ceils. 

Figure 14.10 Overview of cellular entry of (non-viral) gene delivery systems, with subsequent plasmid relocation to the nucleus. The delivery systems (e.g. lipoplexes and polyplexes) initially enter the cell via endocytosis (the invagination of a small section of plasma membrane to form small membrane-bound vesicles termed endosomes). Endosomes subsequently fuse with golgi-derived vesicles, forming lysosomes. Golgi-derived hydrolytic lysosomal enzymes then degrade the lysosomal contents. A proportion of the plasmid DNA must escape lysosomal destruction via entry into the cytoplasm. Some plasmids subsequently enter the nucleus. Refer to text for further details...

Under some circumstances, lysosomal hydrolases may fail to be properly packaged in the TGN, so they enter the default pathway to the cell surface, where they are secreted. Although these hydrolases do little harm at the nearly neutral pH of most extracellular fluids, they can also be returned to lysosomes by a pathway known as receptor-mediated endocytosis. In this pathway, M6P receptors are sent to the plasma membrane, where they bind escaped lysosomal hydrolases and bring them back to lysosomes through the early and late endosomes. Receptor-mediated endocytosis is a major component of the endocytic pathways for trafficking of membrane proteins and merit more detailed consideration. 

Ultrastructural and radioisotope studies on the phagocytosis of particles by gills [84] or lungs [85] demonstrate the endocytosis of particles by mobile macrophages, and their subsequent lysosomal attack. 

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. 

In endocytosis, vesicles are formed at the plasma membrane and then transported to an endosome. (More precisely, endosomes should at least be classified into early endosomes and late endosomes, but this fact is ignored here.) The endocytic pathway also includes the following routes from the endosome to the lysosome, from the endosome to the plasma... 

The distinction between these routes corresponds to the differential uses of transport vesicles (Le Borgne and Hoflack, 1998a) that is, the clathrin-coated vesicles with the adaptor, AP-1, are used in the pathway from the Golgi (TGN) to the endosome the vesicles with clathrin and AP-2 are used in the pathway from the plasma membrane to the endosome (endocytosis itself) and the ones with clathrin and AP-3 seem to be used from the endosome to the lysosome (although there is a dispute on whether or not AP-3 binds to clathrin). 

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