Granzyme K is a protein that functions as a serine protease, playing a part in the body’s defense mechanisms. It belongs to a family of five human granzymes, enzymes stored within immune cells.
Understanding Granzyme K
Granzyme K is a serine protease, an enzyme that breaks down proteins by cleaving peptide bonds. It is primarily located in specialized immune cells, including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). These cells store granzyme K within small sacs called granules, ready for release upon encountering target cells.
Upon activation, these immune cells release granzyme K into the target cell, often with the assistance of a pore-forming protein called perforin. Once inside, granzyme K cleaves specific proteins within the target cell. For instance, it breaks down proteins like nucleosome assembly protein SET, which leads to a form of programmed cell death independent of caspases. Other known targets include heterogeneous nuclear ribonucleoprotein (hnRNP) K, β-tubulin, and α-tubulin.
Granzyme K’s Role in Fighting Infections and Cancer
Granzyme K helps the immune system fight infections and cancer by eliminating compromised cells. When cells are infected or become cancerous, cytotoxic lymphocytes containing granzyme K are deployed. These immune cells recognize abnormal cells and deliver granzyme K to initiate destruction.
Within infected cells, granzyme K directly inhibits viral replication by cleaving specific host proteins like importin-1α and -β. This hinders their nuclear uptake and disrupts the viral life cycle. It also induces cell death in infected cells, preventing pathogen spread. For cancer cells, granzyme K induces cell death by activating pathways, including those independent of caspase activation. This action helps clear diseased cells and maintain health.
Granzyme K and the Body’s Inflammatory Response
Beyond its direct role in cell destruction, granzyme K also influences the body’s inflammatory response. It can act both inside and outside cells to influence inflammation. For example, extracellular granzyme K can activate protease-activated receptor 1 (PAR-1) on cell surfaces.
Activation of PAR-1 by granzyme K phosphorylates ERK1/2, leading to the release of pro-inflammatory cytokines such as IL-1β, MCP-1, IL-6, and IL-8. This process also increases the expression of adhesion molecules like ICAM-1, VCAM-1, and E-selectin, promoting the recruitment of other immune cells to the site of inflammation. Furthermore, granzyme K facilitates the binding between lipopolysaccharides (LPS) and CD14, activating Toll-like receptor 4 (TLR4) signaling and contributing to a pro-inflammatory cytokine response, particularly in bacterial infections.
Granzyme K’s Impact on Health Conditions
Dysregulation of granzyme K can contribute to the progression of various health conditions. Elevated levels of granzyme K have been observed in several diseases, including viral and bacterial infections, airway inflammation, and thermal injury. In conditions like sepsis, increased plasma levels of granzyme K may serve as a diagnostic marker, aiding patient classification and treatment strategies.
Excessive granzyme K activity can contribute to inflammatory diseases, such as psoriasis, by mediating IL-23-dependent inflammation and keratinocyte proliferation. It can also contribute to endothelial microvascular damage and leakage during skin inflammation. Conversely, impaired or insufficient granzyme K function could potentially weaken the immune system’s ability to combat infections or eliminate cancerous cells.