The Evolutionary History of the Chymase Locus -a Locus Encoding Several of the Major Hematopoietic Serine Proteases

Abstract

Several hematopoietic cells of the immune system store large amounts of proteases in cytoplasmic granules. The absolute majority of these proteases belong to the large family of chymotrypsin-related serine proteases. The chymase locus is one of four loci encoding these granule-associated serine proteases in mammals. The chymase locus encodes only four genes in primates, (1) the gene for a mast-cell-specific chymotryptic enzyme, the chymase; (2) a T-cell-expressed asp-ase, granzyme B; (3) a neutrophil-expressed chymotryptic enzyme, cathepsin G; and (4) a T-cell-expressed chymotryptic enzyme named granzyme H. Interestingly, this locus has experienced a number of quite dramatic expansions during mammalian evolution. This is illustrated by the very large number of functional protease genes found in the chymase locus of mice (15 genes) and rats (18 genes). A separate expansion has also occurred in ruminants, where we find a new class of protease genes, the duodenases, which are expressed in the intestinal region. In contrast, the opossum has only two functional genes in this locus, the mast cell (MC) chymase and granzyme B. This low number of genes may be the result of an inversion, which may have hindered unequal crossing over, a mechanism which may have been a major factor in the expansion within the rodent lineage. The chymase locus can be traced back to early tetrapods as genes that cluster with the mammalian genes in phylogenetic trees can be found in frogs, alligators and turtles, but appear to have been lost in birds. We here present the collected data concerning the evolution of this rapidly evolving locus, and how these changes in gene numbers and specificities may have affected the immune functions in the various tetrapod species.

Mast Cell and Basophil Granule Proteases - In Vivo Targets and Function

“…The connective tissue MC proteases efficiently cleaved these anticoagulants whereas the mucosal MC proteases were inactive ( 92 ). This despite the fact that they have a relatively similar cleavage specificity indicating that the difference in specificity is highly relevant for their in vivo function ( 26 ). The connective tissue proteases sit in the skin where they can encounter the anticoagulant proteins from these ectoparasites whereas the mucosal MC proteases are found at other tissue locations where there is little chance to come in contact with these anticoagulants.…”

“…The genes encoding these hematopoietic serine proteases are organized in four different loci, i.e. the MC chymase locus, the MC tryptase locus, the T cell tryptase locus and the met-ase locus ( 25 , 26 ). In mammals, these loci are often located on four different chromosomes, indicating that some of them may originate from whole genome duplications, so called tetraploidizations.…”

“…This massive increase in protease genes in rodent is primarily seen in one of the four loci encoding the hematopoietic serine proteases, i.e. in the chymase locus ( Figure 2 ) ( 25 , 26 ). This locus encodes in humans only four genes, the MC chymase, cathepsin G and two T cell expressed granzymes, the granzymes B and H. In marked contrast, this locus encodes 15 functional protease genes in mouse and as many as 18 such genes in rat ( Figure 2 ).…”

IL-33 induces granzyme C expression in murine mast cells via an MSK1/2-CREB-dependent pathway

“…The roles of MSK1/2 do however appear to be cell-type dependent as in contrast with macrophages MSK1 and 2 are not required for IL-10 induction in LPS-stimulated B cells [ 48 ]. Granzyme C does not possess a direct homologue in human cells; however, granzyme H has been suggested to be the closest human granzyme to murine granzyme C and, similar to granzyme C, is encoded in the chymase locus [ 12 , 49 ]. Alignment of the human granzyme H and mouse granzyme C promoter regions shows the CRE site in the mouse promoter is not conserved in human granzyme H promoter.…”

“…The human genome contains a single chymase gene, Cma1 , followed by cathepsin G, granzyme H, and the granzyme B. In contrast, in mice, more genes are present in this locus with the Cma1 gene, followed by additional chymase genes ( Mpct1 , 9 , 2 , 4 , and then 8 ) before the cathepsin G gene ( Ctsg ) [ 12 ]. While granzyme B is conserved between mice and humans, mice do not have a direct equivalent of granzyme H but instead the locus is expanded to contain genes for granzymes E, D, G, N, F, and C [ 12 ].…”