Degranulation and secretion

Degranulation and secretion are processes whereby the contents of phagocytic storage granules are released into the phagocytic vacuoles (degranulation) or into the extracellular space (secretion). Degranulation and secretion can be triggered by invading micro-organisms, immune complexes, cytokines, chemotactic factors, and adhesion to tissue surfaces and activation of ICAMs. The processes of degranulation and secretion begin with the onset of phagocytosis. A number of morphological changes occur within the granules and they translocate and fuse their membranes with those of the phagocytic vacuoles formed by the invagination of the plasma membrane.

Cytoskeletal proteins are essential for this process facilitating granule transfer to plasma membrane or phagolysosomes. The exact cause of membrane fusion is unknown but the process is likely to involve the activation of several phospholipases leading to altered lipid composition of granule-phagosome or granule-plasma membrane contact points. Actin polymers act like a barrier between plasma membrane and granules, and in order for the membrane fusion to occur the granules have to go through the physical barrier of such cytoskeletal elements in the cell periphery. Furthermore, the repulsive negative charge on the surface of both membranes, related to the negatively charged phospholipids phosphatidylserine and phos-phatidylethanolamine, is a further barrier that needs to be overcome. A number of soluble molecules capable of provoking the release of granule content into the extracellular space have been described. They include many chemotactic factors such as C5a, fMLP, PAF, LTB4, as well as phorbol myristate acetate (PMA) and several non-chemotactic interleukins, cytokines and growth factors such as TNF-a, IL-1, IL-6, IL-4, IL-6 and GM-CSF. Importantly, phagocytes are capable of rapidly replenishing cellular stores of proteins and forming new granules, thus allowing repeated degranulation and secretion.

Regulation of granule release is mediated by a number of factors such as calcium, guanine nucleotides and G-proteins, which regulate changes in the cytoskeleton, resulting in actin polymerization and clearing of the cytoskeleton along the plasma

Cytosolic Proteins

Figure 17.1 Components of the NADPH oxidase system. The components include a 47-kDa cytosolic protein (p47), a 67-kDa cytosolic protein (p67), a 40-kDa cytosolic protein (p40), cytosolic G-proteins (Racl and Papl), and a membrane-bound cytochrome (b558). The cytochrome consists of haem containing p22-phox and gp91-phox. The gp91 subunit is a FAD-dependent flavoprotein shuttling electrons to molecular oxygen, forming O-. The p47

component can be phosphorylated to various extents. In activated cells, the p40, p47 and p67 proteins translocate to membrane to form an activation complex with cytochrome b558. Similarly, the Rac1 and Rap1 proteins also translocate. The activated oxidase passes electrons from NADPH via FAD to oxygen, thereby generating superoxide.

Figure 17.1 Components of the NADPH oxidase system. The components include a 47-kDa cytosolic protein (p47), a 67-kDa cytosolic protein (p67), a 40-kDa cytosolic protein (p40), cytosolic G-proteins (Racl and Papl), and a membrane-bound cytochrome (b558). The cytochrome consists of haem containing p22-phox and gp91-phox. The gp91 subunit is a FAD-dependent flavoprotein shuttling electrons to molecular oxygen, forming O-. The p47

membrane fusion site. These proteins include members of the annexin family, the calcium-binding protein calmodulin, protein kinase C and phospholipases.

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