Granzymes are a family of enzymes found within the human body, serving a significant role in the immune system. These molecular “scissors” are a type of serine protease, meaning they are enzymes that cut other proteins at specific sites. Their primary function involves defense mechanisms, particularly in eliminating cells that pose a threat to the body’s health.
This family of enzymes is packaged within specialized compartments inside certain immune cells. Their precise cutting action allows them to dismantle harmful cells in a controlled manner, preventing widespread damage.
Immune Cells That Use Granzymes
Granzymes are primarily produced and stored by specialized “killer” cells of the immune system: cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. CTLs are part of the adaptive immune system, recognizing and targeting specific threats, such as virus-infected cells or cancerous cells. NK cells, on the other hand, belong to the innate immune system, acting as a first line of defense, providing a rapid response against infections and tumors without prior exposure.
Both CTLs and NK cells store granzymes in specialized compartments called cytoplasmic granules, also known as lytic granules. These granules contain not only granzymes but also other molecules like perforin, a protein that forms pores in the membrane of target cells. When these immune cells encounter a compromised target cell, such as one infected with a virus or a cancerous cell, they form a close connection called an immunological synapse.
The granules then move towards this synapse and release their contents into the small space between the immune cell and the target cell. Perforin creates channels in the target cell’s membrane, allowing the granzymes to enter the target cell’s interior. Once inside, granzymes can initiate the process of programmed cell death.
Granzymes Role in Cell Death
The primary function of granzymes is to induce programmed cell death, known as apoptosis, in target cells. This process is a controlled way for the body to eliminate compromised cells, such as those infected with viruses or cancerous cells, without triggering a strong inflammatory response. Among the granzyme family, Granzyme B is particularly effective at inducing apoptosis.
When Granzyme B enters a target cell, often facilitated by perforin, it initiates a cascade of events. One of its main actions is to directly activate caspases, which are a group of enzymes considered the “executioners” of apoptosis. Granzyme B can cleave pro-caspase-3, leading to its activation, and this activated caspase-3 then cleaves numerous other proteins within the cell, contributing to DNA fragmentation and other hallmarks of cell death.
Granzyme B also plays a role in activating the mitochondrial apoptotic pathway. It can cleave a protein called Bid, which then recruits other proteins like Bax and Bak to the mitochondria. This action changes the permeability of the mitochondrial membrane, leading to the release of cytochrome c and other pro-apoptotic proteins into the cell’s cytoplasm. These released molecules further activate caspases.
Granzymes and Overall Health
Granzymes play a significant role in maintaining overall health by contributing to the body’s defense against various threats. This mechanism is particularly important in fighting viral infections, as granzymes can target and kill cells harboring viruses, and some granzymes can even directly inhibit viral replication by cleaving viral proteins.
Granzymes also contribute to cancer surveillance, where the immune system constantly monitors the body for emerging cancerous cells and eliminates them. Evidence supporting this role includes observations in perforin-deficient mice, which are more susceptible to developing spontaneous and aggressive lymphomas and struggle to reject transplanted tumors.
However, the activity of granzymes can sometimes become dysregulated, leading to negative health consequences. In autoimmune diseases, an overactive granzyme response can cause the immune system to mistakenly attack healthy tissues, leading to tissue damage. For example, Granzyme K has been identified as a driver of inflammation and tissue damage in conditions like rheumatoid arthritis and inflammatory bowel disease by activating the complement system against the body’s own tissues. Similarly, Granzyme B has been implicated in autoimmune skin diseases such as psoriasis and vitiligo, where its excessive activity contributes to inflammation and blistering.
Granzymes are being investigated as potential biomarkers for disease activity or progression, and their pathways are explored as therapeutic targets. Developing inhibitors that specifically target problematic granzymes, such as Granzyme K, could offer more precise treatments for autoimmune and chronic inflammatory conditions, potentially mitigating harmful inflammation while preserving the immune system’s other protective functions.