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Updated: Sep 3, 2025

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Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2

Dion Kaiserman1, Peishen Zhao2,3, Caitlin Lorraine Rowe1

  • 1Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

Plos One
|July 26, 2022
PubMed

Insights

Granzyme K (GzmK) activates protease-activated receptors PAR1 and PAR2. This immune protease acts as a pro-inflammatory regulator by inducing cytokine release, not as a cytotoxin.

Area of Science:

  • Immunology
  • Protease biochemistry

Background:

  • Granzyme K (GzmK) is a serine protease produced by immune cells.
  • Previous research suggested GzmK activates protease-activated receptor 1 (PAR1), promoting monocyte activation and wound healing.

Purpose of the Study:

  • To investigate the ability of Granzyme K (GzmK) and Granzyme A (GzmA) to activate protease-activated receptors (PARs).
  • To elucidate the signaling pathways and cellular responses triggered by GzmK-mediated PAR2 activation.

Main Methods:

  • Utilized peptides and full-length proteins to study GzmK and GzmA interactions with PAR1 and PAR2.
  • Analyzed cleavage events at the canonical arginine P1 residue and exosite interactions.
  • Investigated calcium flux, β-arrestin recruitment, ERK phosphorylation, and cytokine release (IL-6, IL-8) in epithelial cells.

Main Results:

  • GzmK and GzmA activate both PAR1 and PAR2 at the arginine P1 residue.
  • GzmK activation of PAR2 bypasses classical Ca2+ flux, instead recruiting β-arrestin and phosphorylating ERK.
  • GzmK-induced PAR2 activation in A549 cells leads to the release of inflammatory cytokines IL-6 and IL-8.

Conclusions:

  • Granzyme K (GzmK) activates PAR1 and PAR2 through specific protease-receptor interactions.
  • GzmK triggers distinct signaling pathways via PAR2 activation, involving β-arrestin and ERK.
  • These findings suggest GzmK functions as a pro-inflammatory mediator during immune responses, rather than a cytotoxic agent.

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