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Granzyme B's dual role: a fascinating shift from destroying external pathogens to protecting oneself!
Granzyme B (GrB) is a key serine protease present in the granules of natural killer cells (NK cells) and cytotoxic T cells and is essential for their function. This enzyme is secreted together with perforin and promotes apoptosis of target cells. However, Granzyme B goes beyond simply eliminating pathogens and begins to exhibit a miraculous transformation toward self-protection. In this article, we will explore in depth the structure, mechanism of action of Granzyme B and its role in various diseases.
Structure and activity
In humans, Granzyme B is encoded by the GZMB gene, located on chromosome 14. This gene is approximately 3.2kb long and consists of 5 exons. Granzyme B is the most abundant of the five granzymes in humans and has a special structure and is more active at lower concentrations compared to the ten granzymes in mice.
Granzyme B activation usually starts from an inactive proenzyme form, which becomes active after cleavage by protease C and protease H.
Granzyme B's structure consists of two six-stranded β-sheets and three transmembrane segments; this structure is designed to enable it to be activated at neutral pH, but remain inactive in acidic environments to prevent cytotoxic T cells from undergoing auto-apoptosis.
Release and mediated apoptosis
Granzyme B is released simultaneously with perforin, which inserts into the membrane of the target cell, forming small holes that allow Granzyme B to enter the target cell. Using multiple pathways, Granzyme B can enter cells and trigger a series of apoptotic pathways, specifically cleaving and activating initiator and executioner caspases.
Granzyme B activates apoptotic pathways including BAX/BAK polymerization promoted by cleavage of BID, leading to the release of cytochrome c in mitochondria.
Multiple Targets of Granzyme B
Granzyme B exhibits multi-target properties and can act on hundreds of substrates both inside and outside cells. In the cell nucleus, it cleaves several key proteins involved in DNA repair and viral replication. In the extracellular matrix, Granzyme B can degrade various proteins, thereby inducing inflammation and causing cell apoptosis.
The activity of Granzyme B not only affects the apoptotic pathway, but also may trigger local inflammatory responses and has the potential to promote immune responses.
Regulation and inhibition
Notably, the activity of Granzyme B is regulated by several inhibitors, the most common of which is SERPINB9 (also known as PI-9). This protein is expressed in different cell types to protect themselves from Granzyme B-mediated cell death.
Granzyme B's role in diseasePI-9 can form a stable allosteric form with Granzyme B, inhibiting its function and preventing potential self-harm.
The expression level of Granzyme B is normally maintained in the range of 20 to 40 pg/ml, but it is generally increased in a variety of diseases and is closely related to autoimmune diseases, skin diseases and other chronic lesions. For example, its role in rheumatoid arthritis and chronic obstructive pulmonary disease has attracted extensive research attention.
Granzyme B's role in disease-related autoantigen production and its importance in cell death suggest its importance in immune persistence of infection and tissue damage.
As scientists gain a better understanding of Granzyme B's role, they are working to uncover its dual role in health and disease. This makes us wonder whether Granzyme B can become a potential target in disease prevention and treatment in the future?
