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The cell. 5. Vesicular traffic.

LYSOSOMES

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Intracellular degradation of molecules takes place in lysosomes.

Molecules are degraded in lysosomes by enzymes known as acid hydrolases, which show high activity in acid environments. These enzymes arrive to lysosomes from the TGN of the Golgi complex, via late endosomes.

Molecules to be degraded in lysosomes may follow three pathways:

Endocytosis, early endosomes, multivesicular bodies, late endosomes and lysosomes.

Phagocytosis, phagosome and fusion with lysosomes.

Autophagy: cytosolic content, including some organelles, is surrounded by membranes and becomes an autophagosome, which fuses with lysosomes.

Lysosomes, under certain circumstances, may fuse with plasma membrane and release their content to the extracellular space.

Lysosomes are organelles for degradation of molecules coming from endocytosis and autophagocytosis. Contrary to endosomes, they do not contain receptors for mannose-6-phosphate. Metchikoff and coworkers, in the late XIX century, proposed that phagocytosed material is digested in acidic intracellular compartments. Later, these compartments were named as lysosomes, and have been found in all eukaryotic cells. Lysosomes are usually round in shape, membrane-bound organelles of variable size that can be up to 5 % of the total cell volume, percentage that changes along with the digestive activity of the cell.

The pH of lysosomes is about 5, which is the best for the acid hydrolases activity (that is why these enzymes are named "acid"). More than 40 types of acid hydrolases have been found in lysosomes. These enzymes degrade proteins (proteases), lipids (lipases), carbohydrates (glycosidases), and nucleotides (nucleases). The membrane of lysosomes keeps apart acid hydrolases from the rest of the cytoplasm, but even if this membrane breaks, the cytosolic pH, about 7.2, would be basic enough to inhibit the activity of acid hydrolases.

There are different types of lysosomes with different sets of enzymes. Any malfunction of lysosomal enzymes may lead to severe physiological failures because the molecules that should be degraded remain in the cell as residual molecules. For example, type II glycogenolysis (glycogen storage disease) is due to the lack of beta-glucosidase, which catalyzes the glycogen molecules. It causes glycogen accumulation in the organs of the body that could be lethal. Lysosomes are named according to the degradation stage of the molecules they contain: primary lysosomes, secondary lysosomes and residual bodies. Residual bodies contain material that can no longer be degraded. Lysosomes remain in the cytoplasm, or, as we will see later, may fuse with the cell membrane and release their content to the extracellular space.

Lysosomes bear transporters in their membranes that allow the degradation products, such as amino acids, carbohydrates, and nucleotides, to cross the membrane towards the cytosol. Proton pumps are also located in the lysosomal membrane and produce the internal acidic environment. How can molecules located in the inner monolayer of the lysosomal membrane avoid degradation by acid hydrolases? It is thought that the high glycosylation of the inner monolayer molecules protects them from the acid hydrolases.

There are three pathways to lysosomes:

a) Lysosomes are the last station for the degradation endocytic pathway. Molecules in this pathway must travel via endosomes, so that molecules of the endosomal compartments not recycled to plasma membrane or sent back to the TGN of Golgi complex, are driven to lysosomes. How lysosomes are originated is controversial. Some authors propose that they are formed by gemmation or maturation from late endosomes, which already contain the acid hydrolases and molecules for degradation. Other authors suggest that lysosomes are independent organelles that receive vesicles from late endosomes, or that there is a direct fusion between late endosomes and lysosomes.

Integral proteins of the plasma membrane are targeted to lysosomes after the ubiquitination of their cytosolic domain. Ubiquitination is the addition of an ubiquitin protein. The ubiquitinated proteins are recognized by the distribution machinery of early endosomes, which does not select these integral proteins for being included in vesicles shipped to plasma membrane. Ubiquitinated transmembrane proteins are confined to endosomal domains where clathrin is present. So, ubuquitinated proteins are later found in multivesicular bodies / late endosomes, and finally in lysosomes, where they are degraded. This mechanism is used for degradation of membrane receptors, transportes and channels. Non-ubiquitinated integral proteins arriving at early endosomes are included in vesicles back to plasma membrane.

b) Bacteria, virus and cellular fragments engulfed by phagocytosis follow their own way to lysosomes. After they are enclosed by membrane, form a compartment known as phagosome. Degradation takes place when the phagosome fuses with lysosomes.

c) A third pathway for molecules to get to lysosomes is autophagia. It is a cellular ubiquitous process for degrading cytoplasmic material, organelles and cytosolic molecules. Material is enclosed by membranes of the endoplasmic reticulum, and this new membrane bound compartment, known as phagosome, fuses with lysosomes.

Acid hydrolase enzymes must be also targeted to lysosomes because they are the degradation machines. In the TGN of the Golgi complex, these enzymes are included in vesicles and are moved to the multivesicular bodies / late endosomes. We already dealt with how acid hydrolases are selected in the TGN (see figure). In the Golgi complex, a phosphate is added to a mannose of the enzyme. Mannose-6-phosphate is recognized by a membrane receptor in the TGN, and the cytosolic domain of the receptor interacts with adaptor proteins, which in turn interact with clathrin that gathers receptor-hydrolase complexes, which are then included in vesicles directed toward multivesicular bodies/late endosomes. There are other proteins needed by lysosomes that do not follow this process. For example, some transmembrane proteins, such as proton pumps, contain an amino acid sequence in the cytosolic domain recognized by adaptors proteins.

Lysosomes have been long regarded as terminal organelles in the vesicular traffic. However, lysosomes are able to release their content by exocytosis. For example in the liver, bilis contains enzymes released by lysosomes. Melanocytes contain melanin granules, which are thought to be similar to lysosomes. These granules release their content into the epidermis and they are picked up by keratinocytes producing the brown color of the skin after being exposed to the Sun. Sperm acrosome contains lytic enzymes which are released by exocytosis for removing oocyte barriers during fertilization. Furthermore, it has been proposed that some substances that can not be degraded more are stored in lysosomes, which eventually fuse with plasma membrane releasing this content outside of the cell. Finally, lysosomes help repairing cell breakages by fusion with other membrane bound organelles and lately with plasma membrane (see Asymmetry and repairing )

Lysosomal related organelles (LRO)

Some cells contain organelles that can be related to lysosomes because of their molecular content and physiological features, or because they just derive from lysosomes. They are jointly known as LRO (lysosomal related organelles), and include melanosomes of melanocytes, lytic granules of T lymphocytes, dense granules of megakaryocytes, lamellar bodies of the lung type II cells, Weibel-Palade bodies from endothelial cells, and granules of osteoclasts.


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Updated: 2016-08-04. 23:02