Granzyme-K (GrK) is a member of the granzyme family, which are serine proteases primarily involved in the immune system’s cytotoxic response. These enzymes are stored in the granules of cytotoxic cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Granzymes play a crucial role in inducing apoptosis in target cells, thereby contributing to the immune defense against viral infections and tumor cells.
Granzyme-K was first discovered in 1988 after being purified from human peripheral blood mononuclear cells . It is structurally similar to its closest homolog, Granzyme-A (GrA), and displays tryptase-like activity, cleaving substrates after basic amino acids such as arginine or lysine . Granzyme-K contains one peptidase S1 domain, which is characteristic of serine proteases .
Granzyme-K is expressed by various immune cells, including CTLs, NK cells, natural killer T cells (NKT), γδ T cells, and CD56 bright+ NK cells . It is primarily found in the thymus, lung, spleen, and peripheral blood leukocytes . The expression of GrK is upregulated with immune experience, indicating its role in adaptive immunity .
Traditionally, Granzyme-K has been described as a pro-apoptotic enzyme, contributing to the cytotoxicity of immune cells. However, recent studies have revealed additional roles for GrK, both intracellularly and extracellularly .
Granzyme-K has been associated with improved prognosis in solid tumors, suggesting its potential as a therapeutic target . It is predominantly expressed by innate-like lymphocytes and a newly identified population of GrK+ CD8+ non-mucosal-associated invariant T cells with innate-like characteristics . These cells respond to cytokine stimuli alone, indicating their role in the immune response to tumors and infections.