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

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.

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Activation of pro-caspase-7 by serine proteases includes a non-canonical specificity

Biochemical Journal ◽

10.1042/bj3240361 ◽

1997 ◽

Vol 324 (2) ◽

pp. 361-364 ◽

Cited By ~ 106

Author(s):

Qiao ZHOU ◽

Guy S. SALVESEN

Keyword(s):

Aspartic Acid ◽

Serine Proteases ◽

Granzyme B ◽

Cathepsin G ◽

Kinetic Properties ◽

Caspase Activation ◽

Cleavage Specificity ◽

Caspase 7 ◽

Similar Kinetic

As a model to investigate the mechanism of caspase activation we have analysed the processing of pro-caspase-7 by serine proteases with varied specificities. The caspase-7 zymogen was rapidly activated by granzyme B and more slowly by subtilisin and cathepsin G, generating active enzymes with similar kinetic properties. Significantly, cathepsin G activated the zymogen by cleaving at a Gln–Ala bond, indicating that the canonical cleavage specificity at aspartic acid is not required for activation.

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Secretory Granule Proteases in Rat Mast Cells. Cloning of 10 Different Serine Proteases and a Carboxypeptidase A from Various Rat Mast Cell Populations

Journal of Experimental Medicine ◽

10.1084/jem.185.1.13 ◽

1997 ◽

Vol 185 (1) ◽

pp. 13-30 ◽

Cited By ~ 106

Author(s):

Claudia Lützelschwab ◽

Gunnar Pejler ◽

Maria Aveskogh ◽

Lars Hellman

Keyword(s):

Mast Cell ◽

Serine Proteases ◽

Normal Tissue ◽

Cathepsin G ◽

Cdna Libraries ◽

Cdna Clones ◽

Carboxypeptidase A ◽

Effector Cells ◽

Mrna Pool ◽

Rat Mast Cells

Two of the major rat mast cell proteases, rat mast cell protease 1 (RMCP-1) and RMCP-2, have for many years served as important phenotypic markers for studies of various aspects of mast cell (MC) biology. However, except for these proteases only fragmentary information has been available on the structure and complexity of proteases expressed by different subpopulations of rat MCs. To address these questions, cDNA libraries were constructed from freshly isolated rat peritoneal MCs and from the rat mucosal MC line RBL-1. cDNA clones for 10 different serine proteases (RMCP-1-10), and the MC carboxypeptidase A were isolated and characterized. Six of these proteases have not been isolated previously. Based on their protease content, three separate subpopulations of MCs were identified. Connective tissue MCs (CTMCs) from the ear and peritoneum express the chymases RMCP-1 and -5, the tryptases RMCP-6, and -7 and the carboxypeptidase A. However, based on a large difference in the level of expression of RMCP-7, CTMCs of these two organs may be regarded as two separate subpopulations. RMCP-2 and the three closely related proteases of the RMCP-8 subfamily were identified as the major mucosal MC proteases in rat. In contrast to what has been reported for human MCs, no expression of cathepsin G or cathepsin G–like proteases was detected in any of the rat MC populations. To determine mRNA frequencies for the various proteases expressed by normal tissue MCs, an unamplified peritoneal MC cDNA library was screened with a panel of monospecific cDNA probes. These results showed that peritoneal MCs are highly specialized effector cells with mRNA frequencies for the major proteases in the range of several percent of the total mRNA pool.

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Deficient Transcription of Mouse Mast Cell Protease 4 Gene in Mutant Mice of mi/mi Genotype

Blood ◽

10.1182/blood.v93.6.1942.406k08_1942_1950 ◽

1999 ◽

Vol 93 (6) ◽

pp. 1942-1950 ◽

Cited By ~ 42

Author(s):

Tomoko Jippo ◽

Young-Mi Lee ◽

Yee Katsu ◽

Kumiko Tsujino ◽

Eiichi Morii ◽

...

Keyword(s):

Mast Cell ◽

Leucine Zipper ◽

Granzyme B ◽

Mutant Mice ◽

Cathepsin G ◽

Mast Cell Protease ◽

Helix Loop Helix ◽

Regulation Mechanisms ◽

The Difference ◽

Mouse Mast Cell

The mi locus encodes a member of the basic-helix-loop-helix-leucine zipper (bHLH-Zip) protein family of transcription factors (hereafter called MITF). We reported that expression of the mouse mast cell protease 5 (MMCP-5) and MMCP-6 genes were deficient in cultured mast cells (CMC) derived from mutant mice ofmi/mi genotype. Despite the reduced expression of both MMCP-5 and MMCP-6, their regulation mechanisms were different. Because MMCP-5 is a chymase and MMCP-6 a tryptase, there was a possibility that the difference in regulation mechanisms was associated with their different characteristics as proteases. We compared the regulation mechanisms of another chymase, MMCP-4, with those of MMCP-5 and MMCP-6. The expression of the MMCP-4 gene was also deficient in mi/mi CMC. The overexpression of the normal (+) MITF but not of mi-MITF normalized the poor expression of the MMCP-4 gene in mi/mi CMC, indicating the involvement of +-MITF in transactivation of the MMCP-4 gene. Although MMCP-4 is chymase as MMCP-5, the regulation of MMCP-4 expression was more similar to MMCP-6 than to MMCP-5. We also showed the deficient expression of granzyme B and cathepsin G genes inmi/mi CMC. Genes encoding granzyme B, cathepsin G, MMCP-4, and MMCP-5 are located on chromosome 14. Because all these genes showed deficient expression in mi/mi CMC, there is a possibility that MITF might regulate the expression of these genes through a locus control region.

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Potent and Broad but not Unselective Cleavage of Cytokines and Chemokines by Human Neutrophil Elastase and Proteinase 3

International Journal of Molecular Sciences ◽

10.3390/ijms21020651 ◽

2020 ◽

Vol 21 (2) ◽

pp. 651 ◽

Cited By ~ 1

Author(s):

Zhirong Fu ◽

Srinivas Akula ◽

Michael Thorpe ◽

Lars Hellman

Keyword(s):

Mast Cell ◽

Neutrophil Elastase ◽

Human Neutrophil ◽

Serine Proteases ◽

General Pattern ◽

Neutrophil Activation ◽

Cathepsin G ◽

Human Neutrophil Elastase ◽

Proteinase 3 ◽

Cytokines And Chemokines

In two recent studies we have shown that three of the most abundant human hematopoietic serine proteases—mast cell chymase, mast cell tryptase and neutrophil cathepsin G—show a highly selective cleavage of cytokines and chemokines with a strong preference for a few alarmins, including IL-18, TSLP and IL-33. To determine if this is a general pattern for many of the hematopoietic serine proteases we have analyzed the human neutrophil elastase (hNE) and human proteinase 3 (hPR-3) for their cleavage of a panel of 69 different human cytokines and chemokines. Our results showed that these two latter enzymes, in sharp contrast to the two previous, had a very potent and relatively unrestrictive cleavage on this panel of targets. Almost all of these proteins were cleaved and many of them were fully degraded. In light of the proteases abundance and their colocalization, it is likely that together they have a very potent degrading activity on almost any protein in the area of neutrophil activation and granule release, including both foreign bacterial or viral proteins as well as various self-proteins in the area of inflammation/infection. However, a few very interesting exceptions to this pattern were found indicating a high resistance to degradation of some cytokines and chemokines, including TNF-α, IL-5, M-CSF, Rantes, IL-8 and MCP-1. All of these are either important for monocyte-macrophage, neutrophil or eosinophil proliferation, recruitment and activation, suggesting that cytokines/chemokines and proteases may have coevolved to not block the recruitment of monocytes–macrophages, neutrophils and possibly eosinophils during an inflammatory response involving neutrophil activation.

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Crystal chemistry of high-Tc superconductors

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100178720 ◽

1990 ◽

Vol 48 (4) ◽

pp. 1118-1119

Author(s):

Maryvonne Hervieu

Keyword(s):

Oxygen Deficiency ◽

Large Family ◽

Copper Oxides ◽

High Tc Superconductors ◽

High Tc ◽

Single Mechanism ◽

Square Planar ◽

History Of ◽

Bismuth Cuprates ◽

New Compounds

Four years after the discovery of superconductivity at high temperature in the Ba-La-Cu-O system, more than thirty new compounds have been synthesized, which can be classified in six series of copper oxides: La2CuO4 - type oxides, bismuth cuprates, YBa2Cu3O7 family, thallium cuprates, lead cuprates and Nd2CuO4 - type oxides. Despite their quite different specific natures, close relationships allow their structures to be simply described through a single mechanism. The fifth first families can indeed be described as intergrowths of multiple oxygen deficient perovskite slabs with multiple rock salt-type slabs, according to the representation [ACuO3-x]m [AO]n.The n and m values are integer in the parent structures, n varying from 0 to 3 and m from 1 to 4; every member of this large family can thus be symbolized by [m,n]. The oxygen deficient character of the perovskite slabs involves the existence or the co-existence of several types of copper environment: octahedral, pyramidal and square planar.Both mechanisms, oxygen deficiency and intergrowth, are well known to give rise easily to nonstoichiometry phenomena. Numerous and various phenomena have actually been characterized in these cuprates, strongly depending on the thermal history of the samples.

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