L is for lytic granules: lysosomes that kill

Abstract

CTL are important cells in the immune system which are able to recognise and directly destroy virally infected, tumorigenic or foreign cells. The proteins which mediate this destruction are packaged into specialised secretory granules, termed lytic granules, which are secreted in response to target cell recognition. Curiously these specialised secretory granules also contain all the lysosomal hydrolases, and in CTL the lytic granules serve two separate functions: as a lysosome within the cell, and as a secretory granule when a target cell is recognised. These "secretory lysosomes", which serve important roles in both protein degradation within the cells as well as regulated secretion of proteins from the cells, are also found in other cell types, all of which are derived from the hemopoietic lineage. This observation raises the possibility that cells of the hemopoietic lineage possess specialised sorting and secretory mechanisms which allow the lysosomes to be used as secretory organelles. Studies on Chediak Higashi syndrome support this idea, since in this naturally occurring genetic mutation, cells with secretory lysosomes are unable to secrete their granules while other conventional secretory cells are able to do so. Further studies on the mechanisms which regulate secretion of lytic proteins from CTL should identify the proteins involved in this unusual secretory pathway. Some aspects of the differences between conventional and "secretory" lysosomes remain unresolved. How the biogenesis of the secretory lysosome differs from that of a conventional secretory granule is unclear. While conventional secretory cells sort proteins destined for the granule by a selective condensation in the TGN, the secretory lysosomes seem to use a combination of lysosomal and other sorting signals. Our preliminary studies suggest that haemopoietic cells possess specialised sorting mechanisms which allow the correct sorting of the secreted products to the lysosome, and that these signals are different from those found in conventional secretory (e.g. neurosecretory) cells. This finding and the observation that fibroblast lysosomes can undergo calcium-mediated exocytosis suggests that the unusual secretory system found in haemopoietic cells may be a result of specialised sorting mechanisms in these cells. In this case the Chediak lesion may turn out to be a sorting defect.

Dual Role of Signaling Pathways Leading to Ca2+and Cyclic AMP Elevation in Host Cell Invasion byTrypanosoma cruzi

“…Several lines of evidence support the idea that Ca 2ϩ -regulated lysosome exocytosis may be a ubiquitous process that is subverted by T. cruzi as a mechanism for cell invasion. Regulated exocytosis of granules with lysosomal characteristics has been more frequently described in cells of the hematopoietic lineage, such as platelets, mast cells, neutrophils, and cytotoxic lymphocytes (22). Recent evidence indicates, however, that intracellular free Ca 2ϩ elevations can trigger exocytosis of conventional lysosomes in many cell types and that the process may be regulated by a transmembrane protein with Ca 2ϩ -binding properties, synaptotagmin VII (19,26).…”

Human Cathepsin W, a Cysteine Protease Predominantly Expressed in NK Cells, Is Mainly Localized in the Endoplasmic Reticulum

“…In general, two different cytotoxic pathways are known (reviewed in Ref. 5). The first, the perforin-independent lytic pathway, occurs in Ca 2ϩ -free conditions and was found predominantly in CTLs.…”

“…The second, the secretory mechanism, is perforin dependent and was found in both NK cells and CTLs. Here, binding of a target cell by a CTL or NK cell stimulates a Ca 2ϩ -dependent degranulation process in the effector cell that leads to a release of a "death cocktail," causing the subsequent lysis of target cells (5,8).…”

Homotypic Secretory Vesicle Fusion Induced by the Protein Tyrosine Phosphatase MEG2 Depends on Polyphosphoinositides in T Cells

“…Hemopoietic cells use the regulated secretory pathway for a variety of functions (1,2). Platelets contain numerous vesicles with blood clotting factors, vasoactive agents, and growth factors.…”