Granzymes consist exclusively of serine proteases found primarily in the granules of NK cells and cytotoxic T cells of the innate and acquired immune systems. The granzymes are released by degranulation upon recognition of a cell infected with viruses, a tumor cell, or even cells of transplanted foreign tissue. The released granzymes trigger programmed cell death of the target cell after perforin, also released from granules, has created tiny entry ports for the granzymes into the cell membrane.
What are granzymes?
The term granzyme is an acronym derived from the words granules and enzymes. Granules are small intracellular globules of granulocytes that are visible under a microscope. Similar to the larger lysosomes, they are cell inclusions that, in the case of NK cells (natural killer cells) and cytotoxic T cells, contain serine proteases and perforins. Perforins are proteins that can lyse cell membranes to create tiny holes (pores) for granzyme B to enter. It initiates the degradation of DNA in the attacked cell, triggering programmed cell death, or apoptosis. As long as the granules are in the cytoplasm of the immune cells, they are surrounded by a membrane that prevents dangerous contact of the contents with the cytoplasm. Upon contact with a cell that is recognized as worthy of attack, degranulation occurs, in the course of which granules and their contents are expelled from the NK cell or the toxic T cell by exocytosis. Their contents are then released into the extracellular space, immediately in front of the target cell.
Anatomy and structure
The granzymes or serine proteases form a subfamily of the peptidases. Peptidases are enzymes that can break down peptides (extremely short-chain proteins of less than 100 amino acids) and proteins into peptide fragments or individual amino acids. A characteristic feature of a serine protease is its catalytic triad in the active site of the molecule. It is formed from aspartic acid, histidine, and serine, each of whose amino acid residues are linked by hydrogen bonds. It is worth mentioning that one of the three amino acids forming the catalytic triad may be far away from the other two in the two-dimensional model, and the necessary spatial proximity is obtained only by unfolding the molecule into its tertiary structure. Granzyme B, which initiates programmed cell death after penetration through the perforated membrane of the target cell via DNA disruption, is encoded by the GZMB gene. Perforin, which is also present in the granules of granulocytes, is a cytolytic protein that can integrate into the membrane of the target cell and form tiny pores (access ports for the proteases).
Function and roles
The most important task of granzymes is to degrade the DNA of attacked cells or to modify it in such a way that, in the case of virus-infected cells, the viral RNA can no longer replicate, thus initially stopping virus production. In the case of tumor cells, intervention in their DNA first deactivates their ability to divide and then induces their apoptosis. Apoptosis occurs according to genetically fixed processes and is designed in such a way that as many fragments as possible can be recycled and are available to the metabolism for the reconstruction of cells or for further use in energy production. It can become problematic if cells are not recognized as the body’s own tissue and are instead released by immune cells for attack. This then leads to autoimmune reactions. In order for granzymes to perform their main function, they must be released into the extracellular space in the immediate vicinity of the target cell via the process of exocytosis, and the perforins, which are also released, must perforate the membrane of the target cell by lysis so that the granzymes can pass through the membrane to exert their effect in the cytosol and nuclear cytosol. Granzyme B thereby initiates apoptosis by an initiation process. The role of granzyme B in this process is simply to cleave the cell’s own caspase CPP 32, an enzyme that triggers a chain of enzymatic events that ultimately end in apoptosis and thus in the complete destruction of the cell.
Diseases
The immunological efficacy of granzymes is linked to some prerequisites or conditions that must occur.This means that abnormalities in the prerequisites can have a direct effect on the effectiveness of the granzymes. However, disorders of the granzymes themselves can also lead to similar symptoms. For example, a genetic defect causing hemophagocytic lymphohistiocytosis (HLH) simply results in defective perforin synthesis, which triggers a number of serious disease symptoms, including splenomegaly, phagocytosis of the patient’s own blood cells, and many others. Secondary forms of the disease are also observed, which may be caused by viral or bacterial infection, or by a specific leukemia. Similarly, certain autoimmune diseases, such as rheumatoid arthritis and systemic lupus rythematosus, can occur. Acquired HLH is accompanied by a high fever lasting more than seven days, jaundice, edema, skin rashes, and other symptoms. A very rare disease associated with enzyme B is Rasmussen encephalitis, which mainly affects children under the age of 10. It involves severe chronic inflammation in one of the two hemispheres of the brain. Epileptic seizures, speech disorders, and paralysis of the arms and legs typically occur later in the course of the disease. The cause is probably misdirected cytotoxic killer T cells that attack cells of the brain with enzyme B.
