Granzym

Granzym, commonly referred to in English as granzyme, is a family of serine proteases stored in the cytotoxic granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). They are key effectors of the immune system, contributing to the destruction of virus-infected and transformed cells.

Activation and delivery occur when CTLs and NK cells recognize a target. They release cytotoxic granules containing granzymes and perforin, sometimes along with granulysin. Perforin creates pores in the target cell membrane, enabling granzymes to enter the cytosol. Once inside, granzymes cleave intracellular substrates to trigger cell death, using both caspase-dependent pathways and, in some cases, caspase-independent mechanisms.

The granzyme family includes several members, with granzyme B being the best characterized. Granzyme B cleaves and activates caspases and also cleaves Bid, promoting mitochondrial outer membrane permeabilization and apoptosis. Granzyme A is associated with a caspase-independent form of cell death and can influence inflammatory processes. Other granzymes, such as granzyme K and granzyme M, display distinct substrate specificities and contribute to diverse aspects of immune responses.

Synthesis and regulation involve production as inactive zymogens in the secretory pathway and activation within the cytotoxic granules. Activation often requires proteolytic processing, for example by cathepsin C. Granzymes are stored with perforin and granulysin and released together during degranulation. Their activity is tightly controlled to protect healthy tissue while enabling effective target cell killing.

Clinically, granzymes are important for immune surveillance against infections and cancer. Defects in granzyme pathways can impair cytotoxic function, increasing susceptibility to disease, while dysregulated activity can contribute to inflammatory damage. They are active areas of study in immunology and therapeutic development.