Granule-exocytosis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells constitutes the main pathway for eliminating tumor cells and virus-infected cells from our body. In humans, cytotoxic granules contain perforin and fiveserine proteases called granzymes (GrA, GrB, GrH,GrK, and GrM) that induce cell death by cleaving specific intracellular substrates. Apart from GrAand GrB, however, little is known about the cell death mechanism of GrH, GrK, and GrM. In our lab, we are currently investigating these cell death pathways.
Granzymes activate multiple distinct pathways of cell death with distinct morphological hallmarks that cooperate during cytotoxic lymphocyte cytotoxicity. This redundancy likely evolved to provide protection against tumor cells with diverse strategies to evade immune surveillance. Some tumors can escape from GrB-mediated apoptosis by cytoplasmic expression of the GrB-inhibitor serine protease inhibitor (SERPIN)B9. Unlike GrB, however, inhibitors against the other human granzymes remain unknown. This issue currently is another focus in our lab.
We have recently demonstrated that GrM blocks cytomegalovirus replication in the absence of host cell apoptosis. Apparently, GrM uses noncytotoxic mechanisms to inhibit cytomegalovirusreplication, which is compatible with the notion that viruses encode inhibitors of apoptosis. Currently, we are investigating how granzymes block virus replication independent of apoptosis.
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