granzymes

Granzymes are a family of serine proteases released by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to eliminate target cells, including virus-infected and transformed cells. They are stored in cytotoxic granules and delivered to targets during immune synapse formation.

When a CTL or NK cell recognizes a target, it releases granules containing perforin and granzymes into the synaptic cleft. Perforin forms pores in the target cell membrane, allowing granzymes to enter the cytoplasm (either directly through pores or via endocytosis followed by endosomal escape). Once inside, granzymes cleave a range of intracellular substrates to trigger programmed cell death.

Granzyme B is the best characterized and is known to cleave procaspases, promoting the caspase cascade, and to cleave BID, triggering mitochondrial outer membrane permeabilization. Granzyme A is associated with a caspase-independent pathway and can damage multiple substrates, contributing to cell death. In humans, several other granzymes (such as granzyme H, K, M, and others) contribute to cytotoxic activity, each with distinct substrate preferences and roles.

Regulation of granzyme activity involves intracellular inhibitors, notably serpins such as PI-9 (proteinase inhibitor 9), which can limit granzymes to protect cells from unintended damage and modulate immune responses.

The granzyme–perforin pathway is central to immune defense against infections and cancer. It is a focus of research in immunology and immunotherapy, with implications for understanding immune surveillance and the management of immune-related diseases.