Granzyme K drives a newly-intentified pathway of complement activation

Area of Science:

• Immunology
• Protease Function
• Complement System Biology

Background:

• Granzymes are serine proteases primarily from cytotoxic lymphocytes, known for cell death induction.
• Emerging evidence indicates granzymes can modulate inflammation via extracellular substrates.
• Grancyme K (GZMK) is abundant in CD8+ T cells within inflamed tissues like rheumatoid arthritis synovium, but its function is unclear.

Purpose of the Study:

• To elucidate the function of Grancyme K (GZMK) in inflammatory contexts.
• To investigate the role of GZMK in the complement cascade.
• To identify the cellular sources and targets of GZMK-mediated complement activation in rheumatoid arthritis.

Main Methods:

• Biochemical assays to assess GZMK's proteolytic activity on complement components.
• Analysis of complement cascade activation products.
• Immunohistochemical analysis of GZMK and complement components in rheumatoid arthritis synovium.
• Identification of cell types producing complement proteins in inflamed tissue.

Main Results:

• GZMK directly cleaves complement components C2 and C4, initiating complement cascade activation.
• GZMK-driven activation generates C3 and C5 convertases, leading to anaphylatoxins, opsonins, and the membrane attack complex.
• GZMK is localized with complement activation sites in RA synovium, and fibroblasts are key producers of complement targets.
• This represents a novel, lymphocyte-driven complement activation pathway independent of classical, lectin, or alternative routes.

Conclusions:

• GZMK initiates a unique complement activation pathway, distinct from established routes.
• This GZMK-mediated complement activation contributes significantly to tissue inflammation in rheumatoid arthritis.
• The findings suggest GZMK-driven complement activation is a relevant mechanism in various chronic inflammatory diseases and infections.