Proteolytic cleavage at a specific site within the amino (N) terminal extracellular domain of the receptor generates a new N-terminus, exposing a short peptide that acts as a tethered ligand to activate the receptor and initiate downstream signalling cascades.
The protease-activated receptors (PARs) are a family of four G-protein coupled receptors that respond to protease activity. More recently, however, numerous non-cytotoxic and extracellular roles have been reported for granzymes including: cleavage of extracellular matrix to facilitate migration, direct antiviral effects, immune signalling via activation of cytokines, and activation of cell surface receptors. Classically, granzymes are described as intracellular cytotoxins that kill compromised cells by activating redundant death pathways when delivered by the pore-forming protein, perforin. There are five human granzymes, each with a distinct substrate specificity: GzmA (dimeric tryptase), GzmB (asp-ase), GzmH (chymase), GzmK (monomeric tryptase), and GzmM (met-ase). Granzymes (Gzm) comprise a family of chymotrypsin-like serine proteases primarily produced by cells of the immune system. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This work was funded by a National Health and Medical Research Council Australia Project Grant 1141421 (PIB & AS), a National Health and Medical Research Council Australia Program Grant 490900 (PIB), National Institutes of Health grants NS102722, DE026806, DK118971 and DE029951 (NB) and Department of Defense grant W81XWH1810431 (NB). Received: DecemAccepted: JPublished: July 26, 2022Ĭopyright: © 2022 Kaiserman et al. Chai, University of Central Florida, UNITED STATES (2022) Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2. These data suggest that during an immune response GzmK acts as a pro-inflammatory regulator, rather than as a cytotoxin.Ĭitation: Kaiserman D, Zhao P, Rowe CL, Leong A, Barlow N, Joeckel LT, et al. In epithelial A549 cells, PAR2 activation by GzmK results in the release of inflammatory cytokines IL-6 and IL-8. Despite cleaving PAR2 at the same point as trypsin, GzmK does not induce a classical Ca 2+ flux but instead activates a distinct signalling cascade, involving recruitment of β-arrestin and phosphorylation of ERK. These cleavage events occur at the canonical arginine P1 residue and involve exosite interactions between protease and receptor.
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Here, we show using peptides and full length proteins that GzmK and, to a lesser extent the related protease GzmA, are capable of activating PAR1 and PAR2. Previous studies have indicated that GzmK activates protease-activated receptor 1 (PAR1) enhancing activation of monocytes and wound healing in endothelial cells.
Granzyme K (GzmK) is a tryptic member of the granzyme family of chymotrypsin-like serine proteases produced by cells of the immune system.