The natural killer cell serine protease gene Lmet1 maps to mouse chromosome 10

Cytotoxic lymphocytes play a key role in immune responses against viruses and tumors. Lymphocyte-mediated cytolysis by both cytotoxic T lymphocytes (CTL) and natural killer (NK) cells is often associated with the formation of membrane lesions on target cells caused by exocytosis of cytoplasmic granule serine proteases (granzymes) and a pore-forming protein, perforin. A variety of granzymes have been found to reside within the cytoplasmic granules of cytotoxic lymphocytes, but unlike perforin, isolated serine proteases are not intrinsically lytic. However, a role for serine proteases in cellular cytotoxicity has been supported by the ability of protease inhibitors to completely abrogate lymphocyte cytotoxicity, and the demonstration that serine proteases can initiate DNA fragmentation in target cells transfected or pretreated with a sublytic concentration of perforin. Granzymes cloned in human, mouse, and rat encode four granzyme activities (tryptase, Asp-ase, chymase, and Met-ase) and all are expressed in either T cells, their thymic precursors, and/or NK cells. In particular, a rat granzyme that cleaves after methionine residues (a Met-ase), but not phenylalanine residues (a chymase), (designated RNK-Met-1; Smyth et al. 1992) and its human equivalent, human Met-ase 1 (designated Hu-Met-1), are unique granzymes (less than 45% identical to any other granzymes) with restricted expression in CD3-NK cells. Previous gene mapping studies have divided the cytotoxic lymphocyte class of serine proteases into three chromosomal groups: 1) HFSP and TRYP2 to chromosome 5q11-q12; 2) a cluster of genes encoding serine proteases, including human granzymes B and H, to chromosome 14 q11-q12; and 3) a cluster of genes encoding serine proteases, including Hu-Met-1 to chromosome 19p13. The unusual chromosomal location of Hu-Met-1 and its preferential expression in NK cells prompted us to clone an equivalent mouse Met-ase-1 gene (designated Lmet1) and examine its chromosomal locus.