Endosome recycling transport

There have been many studies designed to establish whether the endosomal pathway to lysosomes, and the recycling of receptors is the same with clathrin-dependent and clathrin-independent pinocytosis. The pathway appears to be determined in the endosome, with perhaps the lysosome being the default pathway [54]. During this sorting process, some endosomes are transported to the Golgi apparatus and become associated with secretory vesicles. 

Nanoparticles that are internalized into cells by these mechanisms first enter the primary endosomes of the cell and are then transported into sorting endosomes. While some nanoparticles in the sorting endosomes are transported out of the cell by recycling endosomes, the remaining nanoparticles are transported into secondary endosomes that fuse with the lysosomes [107].The surface charge of PLGA nanoparticles is reversed in the acidic lysosome, resulting in their escape into the cytoplasm... 

Most mammalian cells produce cell-surface receptors that specifically bind to apoB-100 and internalize LDL particles by receptor-mediated endocytosis. After endocytosis, the LDL particles are transported to lysosomes via the en-docytlc pathway and then are degraded by lysosomal hydrolases. LDL receptors, which dissociate from their ligands in the late endosome, recycle to the cell surface. 

However, not all proteins proceed directly to their eventual destination. Some proteins relocate from one plasma membrane compartment to another by means of trans-cytosis. Transcytosis involves endocytosis of selected proteins in one membrane compartment, followed by subsequent transport through early endosomes to recycling endosomes and finally translocation to a different membrane compartment, for example from the apical to the basolateral surfaces. Sorting at the TGN and endo-some recycling steps appear to have a primary role in the steady state distribution of proteins in different plasma membrane domains [47], However, selective retention of proteins at the plasma membrane by scaffolding proteins or selective removal may also contribute to normal distributions. Finally, microtubule-motor regulatory mechanisms have been discovered that might explain the specific delivery of membrane proteins to discrete plasma membrane domains [48]. 

Early endosomes are the main sorting station in the endocytic pathway. In their acidic interior (pH 5.9-6.0), the receptor and its ligand can be released. The receptor may be recycled to the surface by vesicles that fuse with the plasma membrane. Material that cannot escape from the early endosomes is further transported via multivesicular bodies to late endosomes and digesting lysosomes that contain a broad spectrum of peptidases and hydrolases in an acidic surrounding [for reviews on endocytosis see Refs. (10-12), for review on clathrin uptake see Refs. (9,13)]. 

Shiga toxin is described as being transported after uptake via clathrin-coated pits from recycling endosomes to the Golgi apparatus (31). 

At this point, the endosome may fuse with vesicles containing newly synthesized or recycling major histocompatibility complex (MHC) antigens. Some of the partially degraded antigenic fragments may form a complex with the MHC and be transported back to the cell surface. There they are presented to the circulating T-helper (Th)... 

Fig. 6.2. Model for how FcRn rescues IgG from catabolism by recycling and transcytosis. IgG and many other soluble proteins are present in extracellular fluids. Vascular endothelial cells are active in fluid phase endocytosis of blood proteins. Material taken up by these cells enters the endosomes where FcRn is found as an integral membrane protein. The IgG then binds FcRn in this acidic environment. This binding results in transport of the IgG to the apical plasma membrane for recycling into the circulation, or to the basolateral membrane for transcytosis into the extracellular space. Exposure to a neutral pFI in both locations then results in the release of IgG. The remaining soluble proteins are channeled to the lysosomal degradation pathway.

Lysosomal proteins are targeted to the lysosomes via the addition of a mannose 6-phosphate signal that is added in the ds-compartment of the Golgi and is recognized by a receptor protein in the frans-compartment of the Golgi. The protein is then transported by specialized vesicles to a late endosome that later matures into a lysosome. The mannose 6-phosphate receptor recycles back to the Golgi for re-use. 

It should be pointed out, however, that not all hormones dissociate from their receptor in the pH 5.5 environment of the endosome [24], Some hormone-receptor complexes require much lower pH values for dissociation to occur. Although not a peptide hormone, the iron-transport protein transferrin is a peculiar example of this phenomenon and should be pointed out. In this case, at the neutral pH of the extracellular fluid transferrin containing bound iron binds to its cell surface receptor and is internalized. In the low pH environment of the endosome, iron becomes dissociated from transferrin, but transferrin remains bound to its receptor. The transferrin receptor, with bound transferrin, is then recycled to the cell surface. With iron no longer bound to the transferrin, the transferrin readily dissociates from its receptor at the neutral pH of the extracellular fluid [25,26]. This mechanism provides for an efficient continual uptake of iron into cells. Unlike transferrin, however, in those instances where peptide hormones have been documented not to be dissociated from their receptor in the endosome compartment, the hormone and receptor are delivered to the lysosomes via fusion of the endosomes with lyso-somes, where both hormone and receptor are degraded [24,27]. The continuous degradation of the receptor with each round of RME eventually leads to a decrease in the number of receptors on the cell surface, a phenomenon called down-regulation. 

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