Granzymes are specialized proteins used by the immune system to destroy threatening cells, such as those infected by viruses or those that have turned cancerous. These molecules function as active agents of cell death, deployed by immune cells to eliminate harmful targets quickly and efficiently. This process represents one of the most direct methods the immune system employs to maintain health.
Identity and Cellular Origin
Granzymes are a family of serine proteases, enzymes that use the amino acid serine in their active site to cleave other proteins. This cutting action executes their function inside the target cell. In humans, there are five main types of granzymes, with Granzyme A and Granzyme B being the most studied and abundant.
These cytotoxic proteins are produced and stored by specific immune cells: Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells. CTLs are part of the adaptive immune system, trained to eliminate specific threats, such as a virus-infected cell. NK cells belong to the innate immune system, acting as immediate responders that attack any cell appearing abnormal or stressed.
Both CTLs and NK cells package granzymes into specialized compartments called lytic granules. The granzymes are kept inactive within these granules through association with a proteoglycan called serglycin, preventing the immune cell from accidentally destroying itself. This storage mechanism ensures the destructive power of granzymes is only unleashed when a target cell has been correctly identified.
The Delivery System Perforin and the Lytic Granule
For granzymes to function, they must be delivered from the lytic granule into the target cell’s cytosol. This delivery requires the assistance of perforin, a separate pore-forming protein also stored within the lytic granules. Perforin is structurally related to components of the complement system.
When an immune cell recognizes a target, it forms a tight junction called an immunological synapse. The lytic granules move toward this contact point and fuse with the immune cell’s membrane, releasing granzymes and perforin into the synapse. Perforin then inserts itself into the membrane of the target cell in the presence of calcium ions.
Multiple perforin molecules then assemble into a ring-like structure, creating a transient channel or pore in the target cell’s membrane. This pore acts as the entryway, allowing granzyme molecules to pass through and gain access to the cell’s interior. Without functional perforin, granzymes remain outside the target cell and cannot initiate cell death.
Molecular Pathways of Targeted Cell Death
Once Granzyme B is successfully delivered into the target cell’s cytosol, it initiates a rapid and irreversible process of programmed cell death known as apoptosis. Granzyme B is a caspase-like protease, meaning it prefers to cut proteins after specific aspartic acid residues.
Granzyme B directly activates the target cell’s caspases, such as pro-caspase-3, by cleaving them into their active forms. These activated caspases then trigger a cascade that dismantles the cell from the inside out.
In a separate but parallel action, Granzyme B directly cleaves the pro-apoptotic protein BID, transforming it into its active form, tBID. The newly activated tBID protein travels to the mitochondria, where it causes the release of pro-death molecules, including cytochrome c, into the cytosol.
This release amplifies the caspase cascade, ensuring a lethal threshold of activity is reached and the cell is destroyed. Granzyme B’s dual action of directly activating caspases and disrupting mitochondria makes it a powerful inducer of apoptosis among the granzyme family.
Granzyme A, the second most abundant granzyme, works through a distinct, caspase-independent pathway to induce cell death. It traffics to the mitochondria where it causes damage, leading to the generation of reactive oxygen species and single-stranded DNA breaks.
This redundancy in molecular pathways, where different granzymes can achieve the same outcome through multiple routes, helps the immune system overcome viral or cancerous evasion strategies.
Role in Immune Surveillance and Pathologies
The primary function of granzymes is immune surveillance: patrolling and eliminating dangerous cells. By inducing apoptosis, granzymes clear cells infected with intracellular pathogens, such as viruses, before they can replicate and spread. This mechanism also plays a major role in eliminating nascent cancerous cells recognized as abnormal threats.
The effectiveness of this system is demonstrated by individuals with genetic defects in perforin function. Such defects prevent granzyme delivery, making individuals highly susceptible to developing certain cancers and severe viral infections.
While designed for defense, the destructive power of granzymes can contribute to various pathologies when their activity is not properly regulated. For example, Granzyme B outside of its intended context has been linked to chronic inflammation and tissue damage, such as rheumatoid arthritis. The enzymes can act on extracellular matrix proteins, leading to unwanted tissue remodeling and inflammation.