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The cell. 5. Vesicular trafficking.

LYSOSOMES

In the late 19th century, Metchikoff and coworkers proposed that phagocytosed material is digested in acidic intracellular compartments. Later, these compartments were named as lysosomes, and they have been found in all eukaryotic cells so far. Contrary to endosomes, lysosomes do not contain receptors for mannose-6-phosphate. Their main function is degrading molecules coming from endocytosis (external environment) and autophagocytosis (internal environment). Currently, they are regarded as key players in sensing the metabolic state of the cell.

1. Morphology

Lysosomes are organelles of variable size, from 100 to 150 nm in diameter, with a limiting membrane. , Depending on the physiological activity of the cell, the lysosomal population may account for 5 % of the total cellular volume. The lysosomal pH is about 5, which is optimal for the acid hydrolases activity (that is why these enzymes are named "acid"). The membrane of lysosomes protect the rest of the cytoplasm from this destructive activity. The internal surface of lysosomal membrane is coated with a layer of carbohydrates of about 8 nm in thickness, which is known as "lysosomal glycocalyx". These carbohydrates are part of glycoproteins and glycolipids of the membrane and make a physical barrier that prevents acid hydrolases to be in contact with and degrade de membrane. However, even if lysosomal 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 l sets of enzymes. Any malfunction of lysosomal enzymes may lead to severe physiological failures because the molecules that should be degraded remain inside 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, and 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 specific transporters in their membranes that allow the degradation end-products, such as amino acids, carbohydrates, and nucleotides, to cross the lysosomal membrane towards the cytosol. Proton pumps (v-ATPase: vacuolar proton pump) are also located in the lysosomal membrane for acidifying the internal environment.

2. Functions

Degradation

There are three pathways to lysosomes for molecules to be degraded:

a) Lysosomes are the last station for the degradation endocytic pathway. Molecules in this pathway must reach lysosomes via endosomes. Those molecules of the endosomal compartment not recycled to the plasma membrane or sent back to the TGN of the Golgi apparatus, are driven to lysosomes. How lysosomes are originated is controversial. Some authors propose that they are formed by protrusion or maturation from multivesicular bodies / 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.

Transmembrane proteins of the plasma membrane are targeted to lysosomes after the ubiquitination of their cytosolic domain. Ubiquitination is the addition of ubiquitin proteins. The ubiquitinated proteins are recognized by the distribution machinery of early endosomes, which does not gather these integral proteins for being included in vesicles shipped to plasma membrane. Ubiquitinated transmembrane proteins are concentrated at endosomal domains where clathrin coats are present. So, ubuquitinated proteins are kept in early endosomes, 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, adhesion molecules, transporters and channels. Non-ubiquitinated integral proteins arriving at early endosomes are usually included in vesicles back to plasma membrane.

b) Particles entering the cell by phagocytosis follow a distinct pathway. Bacteria, viruses and cellular fragments are engulfed by phagocytosis and form a compartment that develops and becomes a phagosome. Content degradation takes place when phagosome fuses with lysosomes.

Autophagy
Autophagy

c) A third pathway for molecules to get to lysosomes is autophagy. It is a cellular ubiquitous process for degrading cytoplasmic material, organelles and cytosolic molecules. Lysosomes are involved in the different types of autophagy. For example, in macroautophagy, cytoplasmic material is enclosed by membranes of the endoplasmic reticulum, and this new membrane bound compartment, known as macroautophagosome, fuses with lysosomes and the content is broke down.

Acid hydrolases

Acid hydrolases have to be targeted to lysosomes because they are the degradation machines. About 60 different lysosomal acid hydrolases have been found for degrading proteins (proteases), lipids (lipases), carbohydrates (gycosidases) and nucleotides (nucleases). In the TGN of the Golgi apparatus, these enzymes are included in vesicles and are shipped to the multivesicular bodies / late endosomes. We already dealt with how acid hydrolases are selected in the TGN (see figure). In the Golgi apparatus, a phosphate group 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 coat. Thus, receptor-hydrolase complexes are gathered and included in vesicles targeted to multivesicular bodies/late endosomes, and end up later in lysosomes. There are other proteins needed by lysosomes that do not follow this selection process. For example, some transmembrane proteins, such as proton pumps, contain an amino acid sequence in their cytosolic domain which is recognized by adaptor proteins. Acid hydrolases are necessary for normal functioning of cells. Any mutation in any of these enzymes may cause the accumulation of non-degraded molecules that can end up in several pathologies. For example, non-degraded lipids may cause collateral damages in mitochondria and may inhibit autophagy.

Metabolic sensor

Aysosomes are thought to influence the metabolic state of the cell. Two populations of lysosomes have been identified with different distribution in the cytoplasm. A perinuclear population of lysosomes are involved in molecular degradation, whereas a peripheral population is more related to the sensing of the resource availability for the cell. These peripheral lysosomes are also involved in membrane repairing after plasma membrane breakages.

mTOR (target of rapamycin) is a serine/threonine kinase well conserved during evolution. There are two isoforms: mTORC1 and mTORC2. mTORC1 influences cell grow and division, and responds to low nutrient levels, growth signals and energy level of cells, by balancing anabolism (synthesis) and catabolism (degradation). mTORC1 is found at the surface of lysosomes, and this location is very important to perform its function. At the lysosomal membrane, there are molecules that can sense the amount and differences of amino acids between inside and outside the lysosome. mTORC1 is activated when there are nutrients enough. When nutrients are low, mTORC1 is inactivated and macroautophagy is triggered (degradation of large amount of cytoplasm). mTORC1 inactivation stimulates the expression of genes that start macroautophagy and the molecular machinery that moves lysosomes from the periphery to the perinuclear region of the cell. This new location of lysosomes facilitates the formation of autophagolysosomes, which are compartments for degradation of macroautophagy material, and, therefore, as a source of energy for the cell.

In this intense degradation process related to macroautophagy, there is an increase of the lysosomal activity, but, at the same time, a decrease in the number of lysosomes, because they get fused with autophagosomes to form the autophagolysosomes (compartments where degradation takes place). There is mechanism known as ALR (autophagic lysosome formation) that allows the formation of new lysosomes from tubules generated from the autophagolysosome membranes. New vesicles are budded from the tips of these tubules, that once free are actually proto-lysosomes that grow and mature (get more acid) until they become functional lysosomes. The lysosomal population is in this way regenerated. There are many proteins involved in this mechanism, such as phosphoinositides, AP2 adaptor proteins, clathrin, dynamin, microtubules and kinesins.

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 )

Exocytosis

IIt has been long thought that lysosomes have very little connection with vesicular trafficking, and they were regarded as a terminal compartment. However, many evidences have being reported about lysosomes involved in exocytosis processes. For example, in the liver, several lysosomal enzymes are released and are part of bile. Melanocytes may release melanosomes (granules with melanin that are taken by keratynocytes and give a dark color to the skin), which share similar features with melonocyte lysosomes. The sperm achrosome is a vesicle full of hydrolytic enzymes, which is released during fertilization. It has also been proposed that cells may get rid of waste products (molecules that cannot be longer degraded) by lysosomal fusion with the plasma membrane. Lysosmes are also involved in repairing large breakages of the plasma membrane by helping with their own membrane as a patch (see Membrane repairing).

3. 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 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 granule of osteoclasts.

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