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Mystery of Granzyme B: Why is this enzyme so critical in the immune system?
Granzyme B (GrB) is one of the most common serine proteases of natural killer cells (NK cells) and cytotoxic T cells. This enzyme is secreted by these cells and works together with the pore-forming protein perforin to promote apoptosis of target cells. However, the role of Granzyme B is not limited to apoptosis. It plays multiple roles in the immune system and has an important impact on many immune-related diseases. This article will take a closer look at the functions of Granzyme B and its importance in the immune system.
Structure and function of Granzyme B
In humans, Granzyme B is encoded by the GZMB gene on chromosome 14. The gene is 3.2 kb in length and contains 5 exons. Granzyme B is the most abundant of the five human granzymes and its origin can be traced back to a precursor related to granzyme H. Its structure includes two six-stranded β segments and three transmembrane segments. The activity of Granzyme B depends on its amino acid structure. Granzyme B will only become active when the amino-terminal peptide sequence is cleaved by enzymes, which shows its fine regulation in the process of cell apoptosis.
The structure of Granzyme B consists of a catalytic triad including histidine, aspartate, and serine, and prefers the aspartate residue after the P1 position for cleavage.
Release mechanism and apoptotic effect of Granzyme B
The release of Granzyme B is closely related to perforin. When NK cells or cytotoxic T cells recognize target cells, they release perforin to form pores, through which Granzyme B can enter the target cells. Once inside, Granzyme B activates a cascade of enzymes, including initiator caspases (such as caspase 8 and 10) and executioner caspases (such as caspase 3 and 7), thereby triggering the apoptotic process.
Granzyme B can cleave up to 300 substrates and plays a key role in the apoptosis process.
Targets of Granzyme B and their roles in cell death
The effects of Granzyme B are not limited to promoting apoptosis, but also affect multiple substrates in the nucleus and extracellular matrix. For example, it can cleave poly(ADP-ribose) polymerase (PARP) and DNA protein kinase (DNA PK), which interferes with the DNA repair process. In addition, Granzyme B can also degrade a variety of proteins in the extracellular matrix, including fibronectin and vitamins, which can lead to cell death and inflammatory responses.
Granzyme B and autoimmune diseases
Granzyme B concentrations are elevated in many diseases, suggesting that it plays an important role in the pathological process. For example, in type 1 diabetes, Granzyme B promotes apoptosis, leading to the destruction of pancreatic beta cells. In addition, Granzyme B has been directly linked to heart and kidney transplant rejection, making its study imperative.
Granzyme B can generate self-antigens, which can lead to the development of autoimmune diseases.
Regulatory and inhibitory mechanisms
To avoid nonspecific cell death caused by Granzyme B, cells utilize SERPINB9 (also known as protease inhibitor nine) for regulation. The inhibitor works by binding to Granzyme B, rendering it inactive and protecting the cell from itself.
Granzyme B's role in diseaseThe latest research shows that Granzyme B plays a key role in a variety of autoimmune diseases and age-related chronic inflammatory diseases, such as rheumatoid arthritis and chronic obstructive pulmonary disease (COPD). Under these conditions, cell death and extracellular matrix remodeling caused by Granzyme B may aggravate the disease and further lead to more serious consequences. Importantly, experimental models and genetic studies have highlighted the importance of Granzyme B in these processes.
In summary, Granzyme B plays multiple key roles in the immune system, whether it is promoting cell apoptosis or regulating inflammatory responses. This not only reflects its importance in normal physiology, but also makes it a key research object in the development of various diseases. So, given the multiple functions of Granzyme B, how can we effectively use this knowledge to treat related diseases?
