Granzymes

Granzymes

Granzymes are a family of serine proteases that are released by cytotoxic T cells and natural killer cells to induce apoptosis in target cells, such as virus-infected cells or tumor cells. These enzymes play a crucial role in the immune system's ability to control infections and prevent the spread of cancer.

Structure and Function

Granzymes are stored in the cytotoxic granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon recognition of a target cell, these immune cells release their granules into the immunological synapse, allowing granzymes to enter the target cell.

Granzymes are serine proteases, meaning they cleave peptide bonds in proteins. They are synthesized as inactive precursors and become activated upon release. The most well-studied granzymes are Granzyme A and Granzyme B, each with distinct substrates and mechanisms of inducing cell death.

Granzyme A

Granzyme A induces a caspase-independent cell death pathway. It targets the mitochondria and nucleus of the target cell, leading to single-stranded DNA damage and the production of reactive oxygen species.

Granzyme B

Granzyme B is the most potent inducer of apoptosis among the granzymes. It activates the caspase cascade by directly cleaving and activating caspase-3, leading to the classical apoptotic pathway. Granzyme B can also cleave other substrates, such as Bid, a pro-apoptotic Bcl-2 family member, which leads to mitochondrial outer membrane permeabilization and the release of cytochrome c.

Mechanism of Entry

Granzymes enter target cells through a process mediated by the pore-forming protein perforin. Perforin creates pores in the target cell membrane, allowing granzymes to diffuse into the cytosol. Once inside, granzymes can initiate the apoptotic pathways that lead to cell death.

Clinical Significance

Granzymes are essential for the immune system's ability to eliminate infected or malignant cells. Deficiencies in granzyme or perforin function can lead to immune disorders, such as familial hemophagocytic lymphohistiocytosis (FHL), where the immune system fails to control infections and malignancies effectively.

Research into granzymes also has therapeutic implications. Enhancing granzyme activity could improve immune responses against cancer, while inhibiting granzymes might be beneficial in conditions where excessive cell death is detrimental, such as in certain autoimmune diseases.

See Also

• Cytotoxic T cell
• Natural killer cell
• Apoptosis
• Perforin

References

• Trapani, J. A., & Smyth, M. J. (2002). "Functional significance of the perforin/granzyme cell death pathway." Nature Reviews Immunology, 2(10), 735-747.
• Lieberman, J. (2003). "The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal." Nature Reviews Immunology, 3(5), 361-370.