Abstract
Granzymes are a family of serine proteases stored in granules inside cytotoxic cells of the immune system. Granzyme K (GrK) has been only limitedly characterized and knowledge on its molecular functions is emerging. Traditionally GrK is described as a granule-secreted, pro-apoptotic serine protease. However, accumulating evidence is redefining the functions of GrK by the discovery of novel intracellular (e.g. cytotoxicity, inhibition of viral replication) and extracellular roles (e.g. endothelial activation and modulation of a pro-inflammatory immune cytokine response). Moreover, elevated GrK levels are associated with disease, including viral and bacterial infections, airway inflammation and thermal injury. This review aims to summarize and discuss the current knowledge of i) intracellular and extracellular GrK activity, ii) cytotoxic and non-cytotoxic GrK functioning, iii) the role of GrK in disease, and iv) GrK as a potential therapeutic target.
Highlights
Granzymes are a family of serine proteases traditionally known for their role in promoting cytotoxicity of foreign, infected or neoplastic cells
Intracellular GrK-challenged tumor cells are killed in a p53dependent manner [37]. These results identify various intracellular GrK substrates in vitro, including SET, BH3 interacting-domain death antagonist (Bid), apyrimidinic endonuclease 1 (Ape1), vasolin-containing protein (VCP) and p53 leading to cytotoxicity in caspase-independent ways through DNA damage, mitochondrial damage and reactive oxygen species (ROS) accumulation (Figure 1)
In lung diseases such as chronic obstructive pulmonary disease (COPD), hypersensitivity pneumonitis and allergic asthma, roles for GrA and GrB have been reported
Summary
Granzymes are a family of serine proteases stored in granules inside cytotoxic cells of the immune system. Granzyme K (GrK) has been only limitedly characterized and knowledge on its molecular functions is emerging. GrK is described as a granulesecreted, pro-apoptotic serine protease. Accumulating evidence is redefining the functions of GrK by the discovery of novel intracellular (e.g. cytotoxicity, inhibition of viral replication) and extracellular roles (e.g. endothelial activation and modulation of a proinflammatory immune cytokine response). Elevated GrK levels are associated with disease, including viral and bacterial infections, airway inflammation and thermal injury. This review aims to summarize and discuss the current knowledge of i) intracellular and extracellular GrK activity, ii) cytotoxic and non-cytotoxic GrK functioning, iii) the role of GrK in disease, and iv) GrK as a potential therapeutic target
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