Conservation of the Extended Substrate Specificity Profiles Among Homologous Granzymes Across Species

Plasman, Kim; Maurer‐Stroh, Sebastian; Ahmad, Jamshed; Hao, Han; Kaiserman, Dion; Sirota, Fernanda L.; Jonckheere, Veronique; Bird, Phillip I.; Gevaert, Kris; Damme, Petra Van

doi:10.1074/mcp.m113.028670

Cited by 15 publications

(27 citation statements)

References 43 publications

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“…Granzyme C is mouse granzyme located on chromosome 14 and is most closely related to gzmB and it seems to be orthologous to human gzmH (Plasman et al, 2013). It is a 27 kDa protease and its structure reveals an unusual mechanism of protease autoinhibition (Kaiserman et al, 2009).…”

Section: Granzyme C (Rodent Specific)mentioning

confidence: 99%

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Are all granzymes cytotoxicin vivo?

Joeckel

Bird

2014

Biological Chemistry

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Granzymes are serine proteases mainly found in cytotoxic lymphocytes. The most-studied member of this group is granzyme B, which is a potent cytotoxin that has set the paradigm that all granzymes are cyototoxic. In the last 5 years, this paradigm has become controversial. On one hand, there is a plethora of sometimes contradictory publications showing mainly caspase-independent cytotoxic effects of granzyme A and the so-called orphan granzymes in vitro. On the other hand, there are increasing numbers of reports of granzymes failing to induce cell death in vitro unless very high (potentially supra-physiological) concentrations are used. Furthermore, experiments with granzyme A or granzyme M knock-out mice reveal little or no deficit in their cytotoxic lymphocytes' killing ability ex vivo, but indicate impairment in the inflammatory response. These findings of non-cytotoxic effects of granzymes challenge dogma, and thus require alternative or additional explanations to be developed of the role of granzymes in defeating pathogens. Here we review evidence for granzyme cytotoxicity, give an overview of their non-cytotoxic functions, and suggest technical improvements for future investigations.

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Section: Granzyme C (Rodent Specific)mentioning

confidence: 99%

“…Like gzmC, gzmH is a poor cytotoxin as the amount required to kill 50% of target cells is over 170-fold greater than the amount of human gzmB (Plasman et al, 2013). The cytotoxic potential of gzmH has also been studied by the groups of Jenne, Fan and most recently by Bleackley.…”

Section: Granzyme H (Primate Specific)mentioning

confidence: 99%

Are all granzymes cytotoxicin vivo?

Joeckel

Bird

2014

Biological Chemistry

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“…Global proteomics approaches, particularly COFRADIC, are proving very powerful in identifying and refining our understanding of cleavage site preferences of gzms, and comparing/contrasting the profiles of gzm orthologues . There are several advantages compared to classical techniques such as substrate phage or bacterial display, peptide microarrays, mixture‐based oriented peptide libraries, positional scanning peptide libraries, and proteome‐derived, database‐searchable peptide libraries .…”

Section: Proteomic Techniques and Approaches In Gzm Researchmentioning

confidence: 99%

“…GzmH is a chymase‐like protease of 32 kDa and cleaves after phenylalanine and tyrosine. Positional scanning synthetic libraries revealed an optimal P4‐P1 peptide substrate sequence PTSY but the specificities at P4, P3, and P2 are less stringent as several neutral and aliphatic amino acids are tolerated . It is a poor cytotoxin when compared to gzmB (170‐fold less cytotoxic) , however several studies report cytotoxic effects, although they disagree on the biochemical pathway to death .…”

Section: Key Characteristics Associated Diseases and Proteomic Studmentioning

confidence: 99%

Blessing or curse? Proteomics in granzyme research

Joeckel

Bird

2014

Proteomics Clinical Apps

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Granzymes (gzms) are a group of serine proteases that play an important role in innate and adaptive immunity, blood coagulation, apoptosis, and inflammation, but are also connected to atherosclerosis, diabetes, cardiovascular and inflammatory lung diseases, cancer, and sepsis. Humans have five gzms (gzms A, B, H, K, and M), which differ in their substrate specificity. It is widely accepted that they are delivered from cytotoxic lymphocytes via perforin into the cytoplasm of target cells where they initiate cell death, modulate cytokine signaling, or inactivate pathogen proteins. However, more recent evidence indicates gzms also act extracellularly in noncytotoxic processes. Proteomic approaches are directed at mapping gzm cleavage specificity, identifying substrates, and unraveling the (patho-) physiological role of these proteases. These studies have refined our understanding of gzm species specificity, and collectively uncovered an enormous number of new substrates. However, with the exception of a very few human gzmB substrates supported by independent data (Bid, DNA-PK, PARP, ICAD, and procaspase 7), it is presently unclear which are physiologically relevant. This review aims to summarize and analyze the different proteomic approaches used and discuss both their convincing and controversial outcomes.

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“…Humans do not express a direct orthologue to murine granzyme D. However, examining the substrate specificity of the human granzymes (granzymes A, B, H, K and M), it is notable that granzyme H is the only human granzyme family member that has similar activity as granzyme D, i.e. chymotrypsin-like cleavage specificity [16,17,18]. Thereby, granzyme H may represent the closest functional homologue to murine granzyme D. Here, we show that granzyme H is a novel protease expressed by human mast cells.…”

Section: Introductionmentioning

confidence: 99%

Granzyme H Is a Novel Protease Expressed by Human Mast Cells

Rönnberg

Calounova²,

Sutton³

et al. 2014

Int Arch Allergy Immunol

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Background: Many of the functions attributed to mast cells depend on the various pro-inflammatory mediators that are secreted upon mast cell activation. These include a panel of mast cell-specific proteases. In addition, recent studies have indicated that murine mast cells also express granzyme D, a protease previously thought to be confined to cytotoxic lymphocytes. Here, we address the human relevance of the latter findings by investigating whether human mast cells express granzyme H, the granzyme that may represent the functional counterpart to murine granzyme D. Methods: Cord blood-derived mast cells, LAD2 cells and skin mast cells in situ were evaluated for their expression of granzymes using quantitative PCR, Western blot analysis and immunostaining. Mast cells were activated by either calcium ionophore stimulation or IgE receptor cross-linking. Results: Cord blood-derived mast cells and LAD2 cells were shown to express granzyme H and B mRNA, while granzyme A, K and M expression was undetectable. Mast cell activation by either calcium ionophore or IgE receptor cross-linking caused down-regulated expression of granzyme H. In contrast, granzyme B expression was up-regulated by the same stimuli. Granzyme H expression was also confirmed at the protein level, as shown by both Western blot analysis and confocal microscopy. Further, we show that granzyme H is expressed by human skin mast cells in situ. Conclusions: The present findings implicate granzyme H as a novel protease expressed by human mast cells and support earlier findings obtained in natural killer cells suggesting that granzymes B and H are reciprocally regulated.

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Conservation of the Extended Substrate Specificity Profiles Among Homologous Granzymes Across Species

Cited by 15 publications

References 43 publications

Are all granzymes cytotoxicin vivo?

Are all granzymes cytotoxicin vivo?

Blessing or curse? Proteomics in granzyme research

Granzyme H Is a Novel Protease Expressed by Human Mast Cells

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