Intercellular communication via the endo-lysosomal system: Translocation of granzymes through membrane barriers

• Published in: Biochimica et biophysica acta Vol. 1824; no. 1; pp. 59 - 67
• Main Authors: Stewart, Sarah E., D'Angelo, Michael E., Bird, Phillip I.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2012
• Subjects: Animals; apoptosis; cell communication; Cell Communication - genetics; Cell Communication - physiology; Cytotoxic lymphocyte; cytotoxicity; Endocytosis; exocytosis; granules; Granzyme; Granzymes - chemistry; Granzymes - metabolism; Granzymes - physiology; Humans; Intracellular Membranes - metabolism; lymphocytes; lysosomes; Lysosomes - metabolism; Lysosomes - physiology; Membrane repair response; Models, Biological; Models, Molecular; neoplasm cells; Perforin; plasma membrane; Pore; Protein Transport; proteolysis; serine proteinases; Static Electricity; CDC; CI-MPR; FHL2; Granzyme; SNARE; EEA1; FITC; Endocytosis; GrB; SLO; PFO; PLY; Perforin; MBV; AD; CH; HPTS; CL; GUV; HEG; GAG; ER; MAC; TMH; CCP; Membrane repair response; Pore; c9; Cytotoxic lymphocyte; PI; CTL; LAMP; NK; TEM
• ISSN: 1570-9639; 0006-3002; 1878-1454; 1878-1454
• DOI: 10.1016/j.bbapap.2011.05.020

Cytotoxic lymphocytes (CLs) are responsible for the clearance of virally infected or neoplastic cells. CLs possess specialised lysosome-related organelles called granules which contain the granzyme family of serine proteases and perforin. Granzymes may induce apoptosis in the target cell when delivered by the pore forming protein, perforin. Here we follow the perforin-granzyme pathway from synthesis and storage in the granule, to exocytosis and finally delivery into the target cell. This review focuses on the controversial subject of perforin-mediated translocation of granzymes into the target cell cytoplasm. It remains unclear whether this occurs at the cell surface with granzymes moving through a perforin pore in the plasma membrane, or if it involves internalisation of perforin and granzymes and subsequent release from an endocytic compartment. The latter mechanism would represent an example of cross talk between the endo-lysosomal pathways of individual cells. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome. ► Delivery of granzymes by perforin is not understood. ► The two models for delivery do not explain all the experimental data. ► This review highlights the major questions that remain in this field.