Antigonococcal Action of Synthetic Peptides from Huaan Proteases Cathepsin G and Granzyme B

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.

Download Full-text

Cloning of a human granzyme B/cathepsin G related gene encoding a novel serine esterase expressed in cytotoxic lymphocytes

Human Immunology ◽

10.1016/0198-8859(90)90273-r ◽

1990 ◽

Vol 29 ◽

pp. 81

Keyword(s):

Granzyme B ◽

Cathepsin G ◽

Cytotoxic Lymphocytes ◽

Serine Esterase ◽

Related Gene ◽

Gene Encoding

Download Full-text

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.

Download Full-text

The 5′ Flanking Region of the Human Granzyme H Gene Directs Expression to T/Natural Killer Cell Progenitors and Lymphokine-Activated Killer Cells in Transgenic Mice

Blood ◽

10.1182/blood.v93.3.963.403k18_963_973 ◽

1999 ◽

Vol 93 (3) ◽

pp. 963-973 ◽

Cited By ~ 2

Author(s):

Debra M. MacIvor ◽

Christine T.N. Pham ◽

Timothy J. Ley

Keyword(s):

Transgenic Mice ◽

Natural Killer ◽

Cell Lines ◽

Reporter Gene ◽

Granzyme B ◽

Lak Cells ◽

Cathepsin G ◽

Lymphokine Activated Killer Cells ◽

H Gene ◽

Flanking Region

Human granzyme H is a neutral serine protease that is expressed predominantly in the lymphokine-activated killer (LAK)/natural killer (NK) compartment of the immune system. The gene that encodes this granzyme is located between the granzyme B and cathepsin G genes on human chromosome 14q11.2. Although the murine orthologue of human granzyme H has not yet been identified, murine granzymes C, D, E, F, and G also lie between the murine granzyme B and cathepsin G genes on murine chromosome 14; murine granzymes C, D, and F are also highly expressed in LAK cells, but minimally in cytotoxic T lymphocytes (CTL). We therefore tested whether the 5′ flanking region of human granzyme H contains the cis-acting DNA sequences necessary to target a reporter gene to the LAK/NK compartment of transgenic mice. A 1.2-kb fragment of 5′ flanking human granzyme H sequence was linked to an SV40 large T-antigen (TAg) reporter gene and used to create six transgenic founder lines. SV40 TAg was specifically expressed in the LAK cells of these mice, but not in resting T or NK cells, in CTL, or in any other tissues. Most mice eventually developed a fatal illness characterized by massive hepatosplenomegaly and disseminated organ infiltration by large malignant lymphocytes. Cell lines derived from splenic tumors were TAg+ and NK1.1+ large granular lymphocytes and displayed variable expression of CD3, CD8, and CD16. Although these cell lines contained perforin and expressed granzymes A, B, C, D, and F, they did not exhibit direct cytotoxicity. Collectively, these results suggest that the 5′ flanking sequences of the human granzyme H gene target expression to an NK/T progenitor compartment and to activated NK (LAK) cells. Mice and humans may therefore share a regulatory “program” for the transcription of NK/LAK specific granzyme genes.

Download Full-text

Synthetic peptides derived from the sequence of human C-reactive protein inhibit the enzymatic activities of human leukocyte elastase and human leukocyte cathepsin G

International journal of peptide & protein research ◽

10.1111/j.1399-3011.1996.tb00865.x ◽

2009 ◽

Vol 48 (5) ◽

pp. 465-476 ◽

Cited By ~ 5

Author(s):

ERAN J. YAVIN ◽

LIN YAN ◽

DOMINIC M. DESIDERIO ◽

MATI FRIDKIN

Keyword(s):

Synthetic Peptides ◽

Human Leukocyte ◽

Enzymatic Activities ◽

Cathepsin G ◽

C Reactive Protein ◽

Leukocyte Elastase ◽

Reactive Protein ◽

Human Leukocyte Elastase

Download Full-text

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.

Download Full-text

The 5′ Flanking Region of the Human Granzyme H Gene Directs Expression to T/Natural Killer Cell Progenitors and Lymphokine-Activated Killer Cells in Transgenic Mice

Blood ◽

10.1182/blood.v93.3.963 ◽

1999 ◽

Vol 93 (3) ◽

pp. 963-973 ◽

Cited By ~ 15

Author(s):

Debra M. MacIvor ◽

Christine T.N. Pham ◽

Timothy J. Ley

Keyword(s):

Transgenic Mice ◽

Natural Killer ◽

Cell Lines ◽

Reporter Gene ◽

Granzyme B ◽

Lak Cells ◽

Cathepsin G ◽

Lymphokine Activated Killer Cells ◽

H Gene ◽

Flanking Region

Abstract Human granzyme H is a neutral serine protease that is expressed predominantly in the lymphokine-activated killer (LAK)/natural killer (NK) compartment of the immune system. The gene that encodes this granzyme is located between the granzyme B and cathepsin G genes on human chromosome 14q11.2. Although the murine orthologue of human granzyme H has not yet been identified, murine granzymes C, D, E, F, and G also lie between the murine granzyme B and cathepsin G genes on murine chromosome 14; murine granzymes C, D, and F are also highly expressed in LAK cells, but minimally in cytotoxic T lymphocytes (CTL). We therefore tested whether the 5′ flanking region of human granzyme H contains the cis-acting DNA sequences necessary to target a reporter gene to the LAK/NK compartment of transgenic mice. A 1.2-kb fragment of 5′ flanking human granzyme H sequence was linked to an SV40 large T-antigen (TAg) reporter gene and used to create six transgenic founder lines. SV40 TAg was specifically expressed in the LAK cells of these mice, but not in resting T or NK cells, in CTL, or in any other tissues. Most mice eventually developed a fatal illness characterized by massive hepatosplenomegaly and disseminated organ infiltration by large malignant lymphocytes. Cell lines derived from splenic tumors were TAg+ and NK1.1+ large granular lymphocytes and displayed variable expression of CD3, CD8, and CD16. Although these cell lines contained perforin and expressed granzymes A, B, C, D, and F, they did not exhibit direct cytotoxicity. Collectively, these results suggest that the 5′ flanking sequences of the human granzyme H gene target expression to an NK/T progenitor compartment and to activated NK (LAK) cells. Mice and humans may therefore share a regulatory “program” for the transcription of NK/LAK specific granzyme genes.

Download Full-text