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The cell. 5. Vesicular traffic.

ENDOCYTOSIS

« Exocytosis Endosomes »

Endocytosis is the process by which vesicles, and other larger compartments, are formed from the plasma membrane. Vesicles contain extracellular material and part of plasma membrane.

Extracellular molecules that are incorporated by vesicles may be specifically recognized by plasma membrane receptors, or may enter the vesicle as non-specific diluted molecules (pinocytosis).

There are several types of endocytosis: clathrin coated vesicles, caveolae, uncoated vesicles, macropinocytosis and phagocytosis.

Phagocytosis is a particular type of endocytosis where large extracellular particles are included in large membrane compartments.

Catching extracellular molecules is essential for cell survival. Some molecules can cross the plasma membrane, either freely or with the help of membrane transporters, channels and ionic pumps. Endocytosis is a way for entering the cell without crossing the plasma membrane. Molecules are included in invaginations (or evaginations) of the plasma membrane that are later transformed in intracellular vesicles. Exocytosis is the fusion of vesicles with plasma membrane in order to release their content to the extracellular space or to leave vesicle membrane molecules as part of the plasma membrane. Endocytosis is the opposite: it introduces extracellular molecules, and part of the plasma membrane, in vesicles, which forms the vesicle membrane. Vesicles detached from the plama membrane are freed in the cytosol and will fused with other cell compartments, mainly endosomes.

Endocytosis

Molecules that are going to be part of the content of the vesicle may be selected by receptor recognition (specific endocytosis) or enter in solution (pinocytosis, nonspecific endocytosis).

During endocytosis, molecules are recognized by plasma membrane receptors, this is a specific way, or are incorporated in solution in the interior of the vesicle, referred as pinocytosis, which is a non-specific way. Lipid domains may facilitate the attraction of some extracellular molecules by electrochemical affinity. It is clear that vesicles, or other type of membrane compartments, detached from the plasma membrane will carry molecules in solution. So, pinocytosis is always present. Pinocytic material is particularly important in a type of endocytosis known as macropinocytosis (see below). It is important to remark that lipids and proteins located in the plasma membrane are entered during endocytosis as part of the vesicle membrane.

Receptor-mediated endocytosis captures specific extracellular molecules by means of receptors located in the plasma membrane. More than 25 receptor types have been found involved in endocytosis. Molecules and small particles, which are at low concentrations in the extracellular space, are efficiently incorporated into vesicles by this mechanism. Molecules (also known as ligands) are recognized by these receptors, and the ligand-receptor complexes gather in small plasma membrane areas where vesicles are going to be formed. After pinching off from the membrane, vesicles, which contain a high concentration of ligands, are moved away from the plasma membrane. Cholesterol is one example of such molecules incorporated by receptor-mediated endocytosis. Cholesterol is incorporated into the cell as part of low density lipoproteins (LDL). LDL contains many cholesterol molecules surrounded by a lipid monolayer where a protein is inserted. When a cell needs cholesterol or there is a high concentration of cholesterol in the blood, many receptors for LDL are synthesized and are moved to the plasma membrane. There, receptors bind LDL particles, and then receptor-LDL complexes move laterally by lateral diffusion and finally are trapped by incipient membrane invaginations. Once formed, vesicles are moved away and fuse with endosomes, where LDL particles are released from their receptors. After that, LDL particles are moved to the lysosomes for degradation and release of cholesterol. Now, cholesterol can be used by the cell. When this pathway is damaged, for example, by lack of LDL receptors or by failures on the receptor-LDL recognition, cholesterol accumulates in the blood and may cause arteriosclerosis and heart attack.

Types of endocytosis

Types of endocytosis.

Several types of endocytosis have been described depending on the vesicle size, the material to be incorporated, and the mechanism of vesicle formation. Here, we will deal with the following types of endocytosis: clathrin coated vesicles, caveolae, uncoated vesicles, and macropinocytosis. Phagocytosis is being included here too, but it is a particular mechanism because it captures large particles such as bacteria, viruses, and cellular fragments, which are recognized by receptors and surrounded by membrana, and then introduced into the cell.

Clathrin coated vesicles. This endocytic pathway is the main mechanism for incorporating integral proteins and lipids, both located in the plasma membrane, as well as extracellular molecules with a size smaller than 156 nm, including some viruses. Clathrin coated vesicles are formed in plasma membrane areas where the cytoplasmic protein clathrin is present. In fibroblasts, these areas may be up to 2 % of the total surface of the plasma membrane. Clathrin shows a three arms molecular structure, and when these proteins gather together are able to assemble into a regular pentagonal net. This organization and the way they assemble help in the membrane invagination and final closure of the vesicle. The clathrin assembling produces vesicles of about 120 nm in diameter. Clathrin, however, is not in direct contact with the plasma membrane. Other proteins, known as adaptor proteins, are intermediaries between plasma membrane and clathrin, and are also needed for clathrin assembling. Furthermore, adaptor proteins are needed for the selection of proteins which are going to be incorporated into the vesicles: transmembrane proteins as well as receptor-ligand complexes. Adaptor proteins directly bind to the cytosolic domain of transmembrane proteins, including receptors. Once vesicle is closed and moves away from the plasma membrane, the clathrin scaffold is disorganized, individual clathrin proteins are released into the cytoplasm, and vesicle is now moved to the target compartment, usually early endosomes. Free clathrin molecules are thus able to start another endocytic process.

Caveolae. Caveolae were described in the fifties of the last century by P. Palade after observing animal tissues at transmission electron microscopy. They are small invaginations (45-80 nm) of the plasma membrane that can be observed in most of the eukaryotic cells. It was suggested that most of the caveolae become vesicles (but see below). Caveolae are abundant in endothelial cells, muscle cells and adipocytes. The membrane of the caveolae contains caveolin, as well as other integral proteins linked to glycosylphosphatidylinositol, many sphingolipids (sphingomyelin and glycosphingolipids), and is enriched in cholesterol. The presence of caveolin in a cell is enought to form caveolae. There are around 100 to 200 caveolin molecules in one caveola and there are different types of caveolin in one caveola. Caveolin 1 is expressed in smooth muscle cells and in most of the non muscle cells, and it is necessary for caveolae formation in these cells. Caveolin 2, which can be expressed in the same cells as caveolin 1, is not necessary for caveolae formation. Caveolin 3 is expressed in striated skeletal muscle cells, cardiomyocytes, and in several other non muscle cells, and it is necessary for forming caveolae in these cells. Another protein present in caveolae are known as cavin. It is worthy to notice that caveolae may be observed in the Golgi complex as well. In this way, it has been suggested that vesicles coming from caveolae may work as transporter of certain molecules between plasma membrane and Golgi complex. However, most of those coming from the plasma membrane are fused with early endosomes. Some authors suggest that these endosomes are different from other early endosomes and they propose the name caveosome.

Caveolae carry out a number of functions like modulating signal transduction by gathering receptors of plasma membrane, such as tyrosine kinase receptors. They can also participate in the lipid traffic between plasma membrane and organelles. Choleric toxin, folic acid, and other molecules are entered into the cell by means of caveolae. It has been recently proposed that caveolae may not be so important in cell endocytosis as previously thought because only 5 % of the caveolae become vesicles. However, in some cell types, such as endothelial cells, muscle cells, and adipocytes, caveolae may have a more prominent role in endocytosis. It has also been suggested that caveolae may modulate other types of endocytosis, such as clathrin coated vesicles.

Non-coated vesicles. This type of endocytosis has been proposed because the endocytic vesicles are still formed when both clathrin and caveolae endocytic pathways are inhibited. Some toxins, such as cholera toxin, are incorporated in this type of vesicles. It is largely unknown how is the mechanism of vesicle formation and the molecules selected, but lipid rafts may have some role here. It is also unknown how this endocytic pathway is regulated.

Macropinocytosis. This endocytic mechanism allows to enter large amount of extracellular material as well as large amount of plasma membrane. In the surface of the cell, plasma membrane, together with underlying cytoplasm, can protrude like large waves. The protrusions fall onto the surface of the cell, and the crest of the wave fuses with the flat plasma membrane forming a large membrane compartment inside the cell known as macropinosome. This mechanism relies on some components that also take part in phagocytosis: actin filaments and myosin motor protein. Macropinocytosis is not just for feeding, as in amoebas, but also is useful for the recycling of plasma membrane. It is suggested that macropynocitosis facilitates the transport of large amounts of membrane from the rear of the cell to the front part during cell movement. Furthermore, some bacteria are able to enter the cell by macropinocytosis, avoiding the phagocytic degradation pathway.

Phagocytosis. It is a type of endocytosis that incorporates large particles, such as bacteria, cellular fragments, and viruses. Phagocytosis takes place in macrophages, neutrophils and dendritic cells. For example, macrophages internalize antibodies bound to bacteria or viruses, and are also in charge of removing thousands of erythrocytes every day from the blood. Protozoa, however, use phagocytosis for feeding. Phagocytosis starts with the recognition of the particle by membrane receptors. Then, the cell produces laminar- or pseudopodia-like protrusions in the cell surface, which are a result of actin filaments and myosin motor proteins performance. Protrusions enclose the particle and form a large intracellular compartment known as phagosome, which fuses with lysosomes for particle degradation.


Bibliography

Mayor, S., Pagano, R.E . 2007. Pathways of clathrin-independent endocytosis. Nature reviews in molecular and cell biology. 8:603-612.


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Updated: 20-07-2016. 12:17