Lysosomes, role

Direct evidence for a lysosomal role in the breakdown of intracellular proteins has recently been provided by Dean (1975). In his experiment, pepstatin, a potent inhibitor of cathepsin D, was incorporated into liposomes by sonication of the inhibitor in the presence of a lipid mixture. The relatively stable liposomes fused with the cells and introduced pepstatin into the cell interior. Although the means by which pepstatin became incorporated into lysosomes are not clear, degradation in the treated cells was rapidly inhibited to the extent of about 50%. Dean concluded that he had observed a direct lysosomal effect, because pepstatin did not inhibit any proteinase in cells other than cathepsin D, and cathepsin D is totally localized in lysosomes. 

Jentsch, TJ (2007) Chloride and the endosomal lysosomal pathway — emerging roles of CLC chloride transporters. J Physiol 578. 3 663-640... 

As indicated above, Man 6-P serves as a chemical marker to target certain lysosomal enzymes to that organelle. Analysis of cultured fibroblasts derived from patients with I-cell (inclusion cell) disease played a large part in revealing the above role of Man 6-P. I-cell disease is an uncommon condition characterized by severe progressive psychomotor retardation and a variety of physical signs, with death often occurring in the first decade. Cultured cells from patients with I-cell disease were found to lack almost all of the normal lysosomal enzymes the lysosomes thus accumulate many different... 

Osteoclasts are multinucleated cells derived from pluripotent hematopoietic stem cells. Osteoclasts possess an apical membrane domain, exhibiting a ruffled border that plays a key role in bone resorption (Figure 48-12). A proton-translocating ATPase expels protons across the ruffled border into the resorption area, which is the microenvironment of low pH shown in the figure. This lowers the local pH to 4.0 or less, thus increasing the solubility of hydroxyapatite and allowing demineralization to occur. Lysosomal acid proteases are released that digest the now accessible matrix proteins. 

Figure 48-12. Schematic illustration of some aspects of the role of the osteoclast in bone resorption. Lysosomal enzymes and hydrogen ions are released into the confined microenvironment created by the attachment between bone matrix and the peripheral clear zone of the osteoclast. The acidification of this confined space facilitates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases. Bone matrix is thus removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, probably digested further, and transferred into capillaries. The chemical equation shown in the figure refers to the action of carbonic anhydrase II, described in the text. (Reproduced, with permission, from Jun-queira LC, Carneiro J BasicHistology. Text Atlas, 10th ed. McGraw-Hill, 2003.)...

In neurons and non-neuronal cells, kinesin is associated with a variety of MBOs, ranging from synaptic vesicles to mitochondria to lysosomes. In addition to its role in fast axonal transport and related phenomena in non-neuronal cells, kinesin appears to be involved in constitutive cycling of membranes between the Golgi and endoplasmic reticulum. However, kinesin is not associated with all cellular membranes. For example, the nucleus, membranes of the Golgi complex and the plasma membrane all appear to lack kinesin. Kinesin interactions with membranes are thought to involve the light chains and carboxyl termini of heavy chains. However, neither this selectivity nor the molecular basis for binding of kinesin and other motors to membranes is well understood. 

Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates. Necrosis is characterized by marked dysregulation of ion homeostasis resulting in cell swelling, dilation of mitochondria and the ER and the formation of vacuoles in the cytoplasm [33], Proteases play important roles in the degradation of cells during necrosis. In contrast to apoptosis, where caspases are the key death proteases, calpains and lysosomal proteases (cathepsins B and D, in particular) are major players in necrosis. Caspases may be activated in response to mitochondrial damage and... 

Glauman H, Ballard J. Lysosomes and Their Role in Protein Breakdown, Academic Press, New York, 1987. 

C5a is inactivated by the myeloperoxidase-H202 system, which oxidises a methionine residue (Met 70) on the molecule group A streptococcal endo-proteinases also abolish chemotactic activity of C5a and related compounds. Neutrophil lysosomal enzymes (e.g. elastase and cathepsin G) also destroy C5a chemotactic activity, but as these proteases are inhibited by the serum antiproteinases, a -antiproteinase and a2-macroglobulin, the physiological role of neutrophilic proteases in the inactivation of C5a is questionable. Two chemotactic factor inactivators have been found in human serum an a-globulin that specifically and irreversibly inactivates C5-derived chemotactic factors, and a / -globulin that inactivates bacterial chemotactic factors. These activities are heat labile (destroyed by treatment at 56 °C for 30 min) and are distinct from those attributable to anaphylatoxin inactivator. An apparently specific inhibitor of C5-derived chemotactic activity has also been described in human synovial fluid and peritoneal fluid. This factor (molecular mass of 40 kDa) is heat stable and acts directly on C5a. 

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