Granzyme A is a protein that functions as a serine protease, an enzyme that cleaves other proteins. As a component of the immune system, it defends the body against internal threats. This molecule helps manage and neutralize cells that have become cancerous or infected by pathogens as part of a coordinated response to maintain cellular health.
Where Granzyme A is Found in the Body
Granzyme A is not found freely circulating in high amounts; instead, it is produced and stored by specialized immune cells. The primary producers are Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells. CTLs are part of the adaptive immune system and learn to recognize specific threats, while NK cells are part of the innate immune system, providing a more immediate response.
Within these killer cells, granzyme A is manufactured and packaged into membrane-bound compartments called cytotoxic granules. These granules keep the enzyme safely contained until needed. This compartmentalization prevents damage to the host CTL or NK cell, and the granules are mobilized for release when a target is identified.
The granules, containing granzyme A, are directed toward the point of contact between the immune cell and its target. The contents are released into the small space between the cells, known as an immune synapse. This focused delivery maximizes impact on the target cell while minimizing damage to healthy neighboring tissues.
How Granzyme A Eliminates Threats
The primary function of granzyme A is to induce programmed cell death in targeted cells. It works with a partner protein called perforin, released from the same cytotoxic granules. When immune cells engage a target, perforin creates pores in the target cell’s membrane, allowing granzyme A to enter the cell’s interior, or cytosol.
Inside the target cell, granzyme A initiates a unique, caspase-independent pathway of cell death. This is distinct from the pathway of its counterpart, granzyme B, which relies on activating enzymes called caspases. Granzyme A instead sets off a cascade that impacts the mitochondria, disrupting their function and producing damaging reactive oxygen species (ROS).
This surge in ROS creates significant oxidative stress. Granzyme A’s actions also lead to single-stranded DNA damage, destabilizing the cell’s integrity. The combination of mitochondrial dysfunction and DNA damage culminates in the orderly disassembly of the cell.
Granzyme A’s Role in Inflammation
Beyond killing targeted cells, granzyme A also functions outside of cells as a modulator of inflammation. When cytotoxic cells degranulate, some granzyme A can enter the extracellular environment. Here, it interacts with cells and proteins to amplify inflammatory signals.
Extracellular granzyme A stimulates immune cells like monocytes and macrophages to release inflammatory messenger molecules called cytokines. These cytokines, including TNF-α, IL-6, and IL-1β, are signaling proteins that recruit more immune cells to the area. This activity helps shape the local inflammatory environment to clear infections.
This pro-inflammatory function does not always depend on its enzymatic activity. It can also promote inflammation by cleaving proteins in the extracellular matrix, helping immune cells move more freely. The concentration of granzyme A determines its effect, as lower concentrations promote inflammation while higher concentrations are needed for cell death.
The Dual Nature of Granzyme A in Health and Disease
Granzyme A’s functions create a balance between protecting the body and causing harm. In a healthy immune response, its ability to eliminate virus-infected and tumor cells is beneficial. By triggering cell death, it helps contain viruses and check the growth of malignancies, while its pro-inflammatory activities contribute to a robust defense.
This power can become detrimental if not properly regulated. Elevated or persistent extracellular granzyme A activity is linked to tissue damage in chronic inflammatory and autoimmune conditions. In rheumatoid arthritis, for instance, high levels of granzyme A in joint fluid contribute to the persistent inflammation and joint destruction.
In conditions like sepsis, the widespread inflammatory response can be dangerously amplified by granzyme A. Increased levels of this enzyme are associated with the severity of sepsis, a life-threatening condition caused by the body’s dysregulated response to infection. This dual role highlights how an immune molecule can be both a guardian of health and a contributor to pathology.