The cell. 5. Vesicular traffic.
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Endosomes are organelles working as stations for the reception and delivering of vesicles.
Several types of endosomes have been proposed:
Early endosomes. They receive endocytosis vesicles coming from the plasma membrane, and send other vesicles to the plasma membrane (recycling pathway), and to the Golgi complex. Early endosomes become multivesicular bodies.
Multivesicular bodies. They are originated from early endosomes and receive acid hydrolases from the Golgi complex. They have many internal vesicles that arise by invagination of the endosome membrane.
Late endosomes. They are formed from multivesicular bodies and receive acid hydrolases from the Golgi complex. They become lysosomes.
Transcytosis is an especial vesicular pathway. It starts at a domain of the plasma membrane where endocytic vesicles are formed. The content of these vesicles, directly or through endosomes, is released in another different domain of the plasma membrane.
Regardless of the type of endocytosis, vesicles are fused with an internal membranous compartment known as endosome. Intramecellular compartments formed after phagocytosis and macropinocytosis beccome particular types of endosomes known as phagosome and macropinosome, respectively. Endosomes show an irregular shape, like large bags, although sometimes they form tubular structures. Like the TGN of the Golgi complex , endosomes are stations for receiving and distributing molecules packed in vesicles. Vesicles arrive to endosomes from the plasma membrane and from the TGN of the Golgi complex. From endosomes, vesicles leave toward the plasma membrane or TGN of the Golgi complex, both are pathways for recycling membrane receptors and lipids. However, most of the molecules in the endosomes are transported to lysosomes for degradation.
Two ways of endosomal organization have been proposed:
a) Cells would contain several types of endosomes. Early endosomes close to the plasma membrane that receive vesicles from this membrane. Recycling endosomes located a bit deeper in the cell that deliver vesicles to the plasma membrane and Golgi complex. Multivesicular bodies and late endosomes that receive vesicles containing hydrolases from Golgi complex, and send vesicles for recycling to the Golgi complex. Late endosomes eventually fuse with lysosomes for the degradation of their content. All these types of endosomes are stable compartments and communicate between each other by vesicles.
b) A second hypothesis proposes that endocytic vesicles fuse between each other to form an early endosome close to the plasma membrane. Early endosomes move to the inner cytoplasm, and during the way there is a maturation process promoted by vesicles coming from the Golgi complex and, at the same time, early endosomes deliver vesicles to plasma membrane and Golgi complex. So, They are progressively transformed in multivesicular bodies and late endosomes, and finally they becomes lysosomes by progressive internal acidification, or they fuses with nearby lysosomes. In this way, all the endosomes described so far are actually different stages of a continuous maturation process.
It is not clear yet which of these two proposals are correct or if both of them are working at the same time. However, there are evidences supporting more strongly the maturation mechanism.
Types of endosomes, and main traffic pathways they are involved in.
Early endosomes receive endocytic vesicles or are formed by fusion of endocytic vesicles. They become recycling endosomes when are capable of sending vesicles back to the plasma membrane. The recycling flux can be very intense and returns to the plasma membrane up to 90 % of the proteins and 60 % of the lipids which have been endocytosed previously. It is not easy to distinguish between an early and a recycling endosome. Early/recycling endosomes have an acid pH (around 6.5) compared with the cytosolic pH (around 7.2). This difference is due to ATP-dependent proton pumps located in the endosomal membrane. The slightly acid pH inside the endosomes allows the release of ligands from their receptors. In this way, receptors may be sent back to the plasma membrane by recycling vesicles, whereas the ligands can follow the degradation pathway toward lysosomes. The vesicles arrive or leave endosomes at different spatial domains of the endosomal membrane. Actually, it has been suggested that there are at least four spatial domains in the endosomal membranes: one for receiving endocytic vesicles, one for the departure of recycling vesicles, one for vesicles sent to the Golgi complex, and another one more where membranes protrude and form membrane complexes that will become multivesicular bodies. Some authors suggest that there are other less known domains.
Multivesicular bodies, and late endosomes, are the previous step for degrading endocytosed molecules, which finally occurs in lysosomes by acid hydrolases activity. Molecules for degradation arrive via early endosomes, whereas acid hydrolases are packaged in vesicles in the TGN of the Golgi complex. Proton pumps in the membranes of these endosomes progressively decrease de inner pH and make a favorable ambient for acid hydrolases activity. The optimal activity, at pH 5, is reached in lysosomes. Recycling vesicles carrying receptors and membrane are released from multivesicular bodies / late endosomes back toward the TGN of the Golgi complex.
Multivesicular body (arrowhead) in the dendrite of a motoneuron of the hypoglossal nerve. The multivesicular body contains many inner vesicles and is near a synaptic contact. Scale bar: 250 nm. The tissue has been processed as described in Rind et al., 2005. Post: postsynaptic dendrite; Pre: presynaptic terminal; m: mitochondria; v: vesicles: CS: synaptic contact. (Image kindly provided by Chris von Bartheld. Department of Physiology and Cell Biology, University of Nevada School of Medicine. USA).
Multivesicular bodies were first described regarding their morphological features. They are rounded organelles with a membrane enclosing a variable number of inner vesicles (from two to dozens of them). They can occasionally show some tubular structures. Typically, multivesicular bodies are 250 to 1000 nm in diameter and can move through the cytoplasm by means of microtubules. The inner vesicles (30 to 60 nm in diameter) are formed after small invaginations of the multivesicular body membrane. In this way, it is possible to degrade molecules which are part of the endosomal membrane, and also small cytosolic portions which are incorporated inside each little vesicle. The multivesicular body content may follow several pathways: a) degradation in lysosomes by maturation of the multivesicular body or fusion with a lysosome; b) recycling to the TGN of the Golgi complex by vesicles (in this case is mostly membrane); c) release to the extracellular space by fusion with the plasma membrane. The fusion of multivesicular bodies with the plasma membrane allows the release of the inner vesicles, which are renamed as exosomes. There is still another possibility in the synapses of the nerve tissue, where vesicles from multivesicular bodies may fuse with the plasma membrane. This mechanism is referred as back-fusion, and multivesicular bodies may work as a transient storage for certain molecules. This may explain why this organelle is frequently observed in synaptic terminals. Maturation of multivesicular bodies leads to late endosomes.
The journey of the acid hydrolases. These enzymes are synthesized in the rough endoplasmic reticulum (1), enclosed in vesicles, and moved to the Golgi apparatus (1) where a phosphate group is added to one of their mannoses (2). In the TGN of the Golgi apparatus, mannose-6-phosphate-hydrolases are recognized by membrane receptors (3). The receptor-mannose-6-phosphate-hydrolase complexes are gathered and included in vesicles (3). Vesicles are moved toward the multivesicular bodies/late endosomes, and fuse with them. In these endosomes, the pH is more acid than in the TGN so that mannose-6-phosphate-hydrolases are released from their receptors (4). The receptors are then enclosed again in vesicles and return to the Golgi complex (5). Acid hydrolases remain in the endosomes and eventually will be part of the lysosomes.
The acid hydrolases are synthesized and packaged in vesicles in the endoplasmic reticulum and, after being transiently part of the cis domain of the Golgi complex, are then moved to the TGN. In the Golgi complex, a phosphate group is added to one mannose of the hydrolases, and later, in the TGN, hydrolases are segregated from other TGN molecules by a membrane receptor that recognizes the mannose-6-phosphate moiety. Receptor-hydrolase complexes are then gathered in membrane areas enriched in clathrin. Clathrin and other proteins form vesicles that enclose the receptor-hydrolase complexes, move toward multivesicular bodies/late endosomes, and fuse with them. The acidic pH inside these organelles, compared with that of the TGN, triggers the release of hydrolases from their receptors. The phosphate group of the hydrolases is removed and the receptors are packaged again in vesicles going back to the Golgi complex. Meanwhile, hydrolases continue their way toward lysosomes.
The more likely destiny of molecules inside multivesicular bodies/late endosomes is to be degraded in lysosomes. Although not mutually exclusive, two ways have being proposed: maturation of late endosomes by decreasing the internal pH and becoming lysosomes, or by fusion of late endosomes with previously existing lysosomes.
In some cell types, endosomes are involved in other vesicular pathway. When ligand-receptor complexes arrive to early endosomes, ligands are not released but the complexes are packaged again in other vesicles and sent to other plasma membrane domain, different from that where endocytosis happened. Once exocytosis of these vesicles occurs, ligands are released from their receptors in the extracellular space. This vesicular pathway happens in polarized cells, such as epithelial cells. In this way, molecules are endocytosed in one part of the cell, the free apical surface, and released at another part, the latero-basal domain. Molecules can travel from one side to the other without being diverted to lysosomes. By this mechanism, iron-transferrin is transferred from food through the intestine epithelium. This type of transpor is known as transcytosis.
Release of the internal vesicles of multivesicular bodies by fusion with the plasma membrane. These vesicles, once in the extracellular space, are known as exosomes.
Some cell types (hematopoietic cells, dendritic cells, intestine epithelial cells, mastocytes and tumour cells) show some differences in their vesicular traffic. Besides becoming lysosomes, multivesicular bodies are able to fuse with plasma membrane and release their inner vesicles to the extracellular space. These released vesicles, known as exosomes, contain a distinct molecular composition. For example, they contain a high amount of cholesterol and sphingomyelin in their membranes. Exosomes have been proposed as message carriers between cells.
Cabrera M, Ungermann C. 2010. Guiding endosomal maturation. Cell. 141:404-406.
Rind HB, Butowt R, von Bartheld CS. 2005. Synaptic targeting of retrogradely transported trophic factors in motoneurons: comparison of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and cardiotrophin-1 with tetanus toxin. Journal of Neurosciences. 25, 539-549.
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Updated: 2016-07-30. 17:24
Atlas of Plant and Animal Histology
Dep. of Functional Biology and Health Sciences.
Faculty of Biology.
University of Vigo