The GZMA gene, with 7607 bases in length, consists of 5 exons and 4 introns. GZMA gene is located in a gene cluster together with granzyme K (figure 1) (Grossman et al., 2003).

There are at least two transcripts of human GZMA whose expression is differentially regulated by glucocorticoid (Ruike et al., 2007). These transcripts generate two isoforms, GZMAα and GZMAβ, which have respective first exons: exon 1a and exon 1b (figure 1):
GZMAα (exon 1a): canonical sequence,
GZMAβ (exon 1b): lack aa 1-17; aa 18-23 LLLIPE --> MTKGLR.

Granzyme A is a tryptase (cleave proteins after Lys or Arg residues) expressed mainly in cytotoxic cells (cytotoxic T and Natural Killer cells) (Masson et al., 1986; Simon et al., 1986; Young et al., 1986). Protein is expressed as a preproenzyme (Jenne et al., 1988) containing a signal sequence that mediates targeting of the nascent enzyme to the ER. Cleavage of the signal peptide produces an inactive proenzyme that contains an N-terminal dipeptide that needs to be cleaved to produce an active protease. In the Golgi, a mannose-6-phosphate tag is added for transporting the proenzyme to cytotoxic granules. Within the cytotoxic granule, the N-terminal dipeptide is removed by cathepsin C (dipeptidyl peptidase I) (Pham et al., 1999), producing the active enzyme that is kept inactive at low pH. Native granzyme A is expressed as a dimer (Bell et al., 2003; Hink-Schauer et al., 2003).

Cytotoxic CD8+ T cells, Natural Killer cells, CD4+ T cells, gamma-delta T cells, type II pneumocytes, alveolar macrophages, bronchiolar epithelial cells.

Cytotoxic granules.

Granzyme A is delivered from CTL or NK cytotoxic granules to the cytoplasm of target cell by a mechanism dependent on perforin (Baran et al., 2009; Praper et al., 2011; Thiery et al., 2011).
There are some controversial findings about the physiological function of gzmA.
It has been reported that human GzmA induces perforin-mediated caspase-independent cell death in some tumors cell lines (Hayes et al., 1989; Shi et al., 1992; Beresford et al., 1999; Shresta et al., 1999; Pardo et al., 2004). GzmA translocates to the nucleus and mitochondria where key substrates such as mitochondrial complex I protein, NADH dehydrogenase Fe-S protein 3 (NDUFS3) is cleaved, inducing the production of Radical Oxygen Species (ROS). ROS production induces the activation of the SET complex that translocates into the nucleus in order to repair DNA damage induced by ROS. Once there, granzyme A cleaves components of the endoplasmic reticulum-associated SET complex, releasing the endonuclease NM23H1 that induces single strand nicks in the DNA and ultimately cell death (Lieberman, 2011).
Other authors have reported that the cytotoxic potential of granzyme A is low, but induce expression of pro-inflammatory cytokines in monocytes-like cells by a caspase-1 dependent mechanism (Metkar et al., 2008).
Granzyme A is able to cleave several extracellular substrates like thrombin receptor, fibronectin, collagen IV, proteinase-activated receptor-2, Pro-urokinase plasminogen activator and myelin basic protein (Kramer et al., 1987; Buzza et al., 2006; Hendel et al., 2011).
Granzyme and granzyme B double deficient mice are more susceptible than granzyme B deficient mice to transplanted tumors suggesting a contribution of granzyme A to tumor control in vivo (Pardo et al., 2002; Cao et al., 2007).

Mouse granzyme A;
Rat granzyme A;
Chicken granzyme A;
Fish granzyme A (Common Carp, Atlantic cod, Channel catfish) (Praveen et al., 2006; Praveen et al., 2006; Wernersson et al., 2006).

Not known.