Granzyymeilla

Granzyymeilla (granzymes) are a family of serine proteases produced by cytotoxic lymphocytes, primarily CD8+ T cells and natural killer (NK) cells. They are stored in lytic granules alongside perforin and other granule components and are released into the immunological synapse when a cytotoxic cell recognizes a target, such as an infected or transformed cell. The main role of granzyymes is to induce death in these targets through proteolytic pathways that lead to apoptosis or other forms of cell death.

Mechanism and delivery: Perforin forms pores in the target cell membrane, allowing granzymes to enter the cytosol. Once inside, granzymes activate a cascade of proteolytic events. Granzyme B is a potent inducer of apoptosis by activating caspases and cleaving substrates that promote mitochondrial outer membrane permeabilization. Granzyme A is associated with caspase-independent pathways and inflammatory signaling. Different granzymes have distinct substrate preferences and can contribute to diverse death pathways, contributing to the versatility of cytotoxic responses.

Types and regulation: The best characterized human granzymes include GZMA, GZMB, GZMH, GZMK, and GZMM. They are regulated at multiple levels, including storage in granules, delivery through contact-dependent exocytosis, and inhibition by intracellular serpins such as SERPINB9 (PI-9), which protects target cells from granzyme B. Granzyme activity can be modulated by the local cellular environment and by inhibitors present in the immune system.

Clinical and research relevance: Granzymes are central to cytotoxic immune defense against virally infected cells and tumors. Altered granzyme expression or function is studied in immunodeficiencies, infectious diseases, and cancer immunotherapy, where cytotoxic lymphocytes are engineered or expanded to enhance granzyme-mediated killing.