Cytotoxic and Non-cytotoxic Roles of the CTL/NK Protease Granzyme B

The caspase family of cysteine proteases becomes activated in response to diverse cellular insults and coordinates apoptosis through proteolysis of hundreds of cellular substrates. Cytotoxic lymphocytes are adept at promoting apoptosis of virally infected or transformed cells through delivery of cytotoxic enzymes, such as granzyme B, into target cells via the granule exocytosis pathway. Granzyme B promotes apoptosis of target cells through direct processing of certain caspases, which leads to their autoactivation. Granzyme B can also activate caspases indirectly through proteolysis of Bid, a protein that promotes mitochondrial permeabilization and consequent activation of the apoptosome pathway to caspase activation. Evidence also indicates that granzyme B may contribute to antiviral immunity by directly suppressing viral replication through direct proteolysis of viral proteins that are essential for pathogenicity. Recent reports also suggest that granzyme B may have additional non-cytotoxic roles under certain circumstances and may also function in the extracellular space. Here, we discuss the cytotoxic and putative non-cytotoxic functions of granzyme B within the immune system.