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

1997 ◽  
Vol 324 (2) ◽  
pp. 361-364 ◽  
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.

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

2021 ◽  
Vol 22 (20) ◽  
pp. 10975
Author(s):  
Srinivas Akula ◽  
Zhirong Fu ◽  
Sara Wernersson ◽  
Lars Hellman
Keyword(s):  
Mast Cell ◽  
T Cell ◽  
Serine Proteases ◽  
Phylogenetic Trees ◽  
Granzyme B ◽  
Large Family ◽  
Cathepsin G ◽  
Immune Functions ◽  
New Class ◽  
History Of

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.

scholarly journals The three-dimensional structure of human granzyme B compared to caspase-3, key mediators of cell death with cleavage specificity for aspartic acid in P1

2001 ◽  
Vol 8 (4) ◽  
pp. 357-368 ◽  
Author(s):  
Jennifer Rotonda ◽  
Margarita Garcia-Calvo ◽  
Herb G Bull ◽  
Wayne M Geissler ◽  
Brian M McKeever ◽  
...  
Keyword(s):  
Cell Death ◽  
Aspartic Acid ◽  
Caspase 3 ◽  
Granzyme B ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Three Dimensional Structure ◽  
Cleavage Specificity

scholarly journals Selective Regulation of Apoptosis: the Cytotoxic Lymphocyte Serpin Proteinase Inhibitor 9 Protects against Granzyme B-Mediated Apoptosis without Perturbing the Fas Cell Death Pathway

1998 ◽  
Vol 18 (11) ◽  
pp. 6387-6398 ◽  
Author(s):  
Catherina H. Bird ◽  
Vivien R. Sutton ◽  
Jiuru Sun ◽  
Claire E. Hirst ◽  
Andrea Novak ◽  
...  
Keyword(s):  
Proteinase Inhibitor ◽  
Granzyme B ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Caspase Inhibitor ◽  
Caspase Activation ◽  
Cytotoxic Lymphocyte ◽  
Transfected Cells ◽  
Cell Death Pathway ◽  
Proteinase Inhibitor 9

ABSTRACT Cytotoxic lymphocytes (CLs) induce caspase activation and apoptosis of target cells either through Fas activation or through release of granule cytotoxins, particularly granzyme B. CLs themselves resist granule-mediated apoptosis but are eventually cleared via Fas-mediated apoptosis. Here we show that the CL cytoplasmic serpin proteinase inhibitor 9 (PI-9) can protect transfected cells against apoptosis induced by either purified granzyme B and perforin or intact CLs. A PI-9 P1 mutant (Glu to Asp) is a 100-fold-less-efficient granzyme B inhibitor that no longer protects against granzyme B-mediated apoptosis. PI-9 is highly specific for granzyme B because it does not inhibit eight of the nine caspases tested or protect transfected cells against Fas-mediated apoptosis. In contrast, the P1(Asp) mutant is an effective caspase inhibitor that protects against Fas-mediated apoptosis. We propose that PI-9 shields CLs specifically against misdirected granzyme B to prevent autolysis or fratricide, but it does not interfere with homeostatic deletion via Fas-mediated apoptosis.

scholarly journals Extended cleavage specificity of human neutrophil cathepsin G: A low activity protease with dual chymase and tryptase-type specificities

PLoS ONE ◽  
2018 ◽  
Vol 13 (4) ◽  
pp. e0195077 ◽  
Author(s):  
Michael Thorpe ◽  
Zhirong Fu ◽  
Gurdeep Chahal ◽  
Srinivas Akula ◽  
Jukka Kervinen ◽  
...  
Keyword(s):  
Human Neutrophil ◽  
Cathepsin G ◽  
Cleavage Specificity ◽  
Low Activity

scholarly journals Death Receptor-induced Apoptosis Reveals a Novel Interplay between the Chromosomal Passenger Complex and CENP-C during Interphase

2007 ◽  
Vol 18 (4) ◽  
pp. 1337-1347 ◽  
Author(s):  
Alison J. Faragher ◽  
Xiao-Ming Sun ◽  
Michael Butterworth ◽  
Nick Harper ◽  
Mike Mulheran ◽  
...  
Keyword(s):  
Death Receptor ◽  
Caspase 8 ◽  
Cleavage Sites ◽  
Caspase Activation ◽  
Functional Link ◽  
Chromosomal Passenger Complex ◽  
Caspase Cleavage ◽  
Chromosomal Passenger ◽  
Caspase 7 ◽  
Induced Apoptosis

Despite the fact that the chromosomal passenger complex is well known to regulate kinetochore behavior in mitosis, no functional link has yet been established between the complex and kinetochore structure. In addition, remarkably little is known about how the complex targets to centromeres. Here, in a study of caspase-8 activation during death receptor-induced apoptosis in MCF-7 cells, we have found that cleaved caspase-8 rapidly translocates to the nucleus and that this translocation is correlated with loss of the centromere protein (CENP)-C, resulting in extensive disruption of centromeres. Caspase-8 activates cytoplasmic caspase-7, which is likely to be the primary caspase responsible for cleavage of CENP-C and INCENP, a key chromosomal passenger protein. Caspase-mediated cleavage of CENP-C and INCENP results in their mislocalization and the subsequent mislocalization of Aurora B kinase. Our results demonstrate that the chromosomal passenger complex is displaced from centromeres as a result of caspase activation. Furthermore, mutation of the primary caspase cleavage sites of INCENP and CENP-C and expression of noncleavable CENP-C or INCENP prevent the mislocalization of the passenger complex after caspase activation. Our studies provide the first evidence for a functional interplay between the passenger complex and CENP-C.

Hemopoietic Progenitor Cells from the Bone Marrow of Serpinb3A-/- Mice Are Radioresistant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2680-2680
Author(s):  
Stephanie Thermozier ◽  
Michael W. Epperly ◽  
Darcy Franicola ◽  
Xichen Zhang ◽  
Renee Fisher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Progenitor Cells ◽  
Serine Proteases ◽  
Cathepsin G ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
University Of Pittsburgh ◽  
Significant Difference ◽  
The University

Abstract Introduction: Serpins are a superfamily of serine proteases that regulate proteolytic pathways by utilizing a conformational change to bind to and inhibit multiple peptidases. Currently 36 human serpins have been identified, but the roles of most are not fully understood (Silverman et al., J Biol Chem. 285(32):24299-305, 2010). A majority of serpins inhibit serine proteases but serpins that inhibit lysosomal cytosine peptidases, granzymes, serine protease and calpains. Previous studies have shown that serpins play a critical role in cell survival by blocking lysosomal induced necrosis injury. Serpinb3A (Antichymotrypsin) has been identified as an inhibitor of the serine peptidases, chymotrypsin and cathepsin G. We now report that hematopoietic progenitor cells in the bone marrow of Serpinb3A-/- mice are radioresistant. Materials & Methods: Serpinb3A-/- and control Balb/c mice were obtained from Charles River and were housed five per cage according to University of Pittsburgh Institutional Animal Care and Use Committee (IACUC) regulations. All protocols were approved by the University of Pittsburgh IACUC. Veterinary care was provided by the Division of Laboratory Animal Research of the University of Pittsburgh. Whole bone marrow was obtained by flushing the marrow from the femurs of sacrificed Serpinb3A-/- and Balb/c mice. Single cell suspensions were irradiated to doses ranging from 0 to 8 Gy using a at 70 cGy/min using a Shepherd Mark 1 137Cs γ-ray source (J.L. Shepherd, San Fernando, CA, USA). The cells were plated in 0.8% methylcellulose containing hematopoietic growth supportive medium (StemCell Technology product #3134) at varying densities in quadruplicate in Linbro plates (Fisher Scientific, Pittsburgh, PA, USA) and incubated at 37°C and 5% CO2 for 9-11 days at which time the number of colony forming unit granulocyte-macrophage (CFU-GM) colonies of 50 cells or greater were counted. The data from 5 experiments was analyzed using linear quadratic and single-hit, multi-target models. Results: CFU-GM from Serpinb3A-/- mouse marrow showed an increase in radiation resistance with an increase in the shoulder of the irradiation survival curve compared to Balb/c marrow (ň = 4.9 ± 1.4 and 1.4 ± 0.1, p = 0.0451, respectively). There was no significant difference in the Do for CFU-GM of the two mouse strains (Do = 1.48 ± 0.19 Gy for Serapinb3A-/- mice and 1.56 ± 0.06 Gy for Balb/c mice, p = 0.0997. Conclusions: The data support a possible role for the loss of Serpinb3a in providing a cell survival advantage for hematopoietic progenitor cells exposed to lethal doses of ionizing irradiation. This would suggest that the Serpinb3a target protease helps repair the cellular injury induced by ionizing radiation. Alternatively, the germ line loss of Serpinb3a may up-regulate the expression of other clade B serpins known to protect cells from injury. Ongoing studies will help determine the nature of this protective effect against radiation-induced cell death. Disclosures No relevant conflicts of interest to declare.

scholarly journals A tick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 736-744 ◽  
Author(s):  
Jindrich Chmelar ◽  
Carlo J. Oliveira ◽  
Pavlina Rezacova ◽  
Ivo M. B. Francischetti ◽  
Zuzana Kovarova ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Serine Proteases ◽  
Acute Inflammation ◽  
Biological Activities ◽  
Salivary Protein ◽  
Cathepsin G ◽  
Skin Injury ◽  
Edema Formation ◽  
Protein Targets ◽  
First Time

Abstract Platelet aggregation and acute inflammation are key processes in vertebrate defense to a skin injury. Recent studies uncovered the mediation of 2 serine proteases, cathepsin G and chymase, in both mechanisms. Working with a mouse model of acute inflammation, we revealed that an exogenous salivary protein of Ixodes ricinus, the vector of Lyme disease pathogens in Europe, extensively inhibits edema formation and influx of neutrophils in the inflamed tissue. We named this tick salivary gland secreted effector as I ricinus serpin-2 (IRS-2), and we show that it primarily inhibits cathepsin G and chymase, while in higher molar excess, it affects thrombin activity as well. The inhibitory specificity was explained using the crystal structure, determined at a resolution of 1.8 Å. Moreover, we disclosed the ability of IRS-2 to inhibit cathepsin G-induced and thrombin-induced platelet aggregation. For the first time, an ectoparasite protein is shown to exhibit such pharmacological effects and target specificity. The stringent specificity and biological activities of IRS-2 combined with the knowledge of its structure can be the basis for the development of future pharmaceutical applications.

Sign in / Sign up

Export Citation Format

Share Document