Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H...

Area of Science:

• Immunology
• Biochemistry
• Molecular Biology

Background:

• Extracellular matrix (ECM) components can trigger complement activation and inflammation when exposed to body fluids.
• Pathological complement activation in renal and eye diseases is linked to glomerular and Bruch's membranes.
• Factor H (FH) is a crucial soluble complement inhibitor that binds to ECM to prevent excessive complement activation.

Purpose of the Study:

• To investigate if FH-related (FHR) proteins FHR1 and FHR5 bind to ECM components.
• To determine if FHR1 and FHR5 affect local FH activity and complement activation.
• To identify specific binding domains of FHR1 and FHR5 to ECM and complement components.

Main Methods:

• Assessed binding of FH, FHR1, and FHR5 to various ECM components using biochemical assays.
• Identified binding domains on FHR1 and FHR5 using complement control protein (CCP) domain mapping.
• Measured FH cofactor activity and alternative complement pathway activation on ECM-bound proteins in human serum.

Main Results:

• FHR1 and FHR5 bind to specific ECM components including laminin, fibromodulin, osteoadherin, and PRELP.
• FHR1 and FHR5 competitively inhibit FH binding to ECM, reducing FH's cofactor activity.
• FHR1 and FHR5 enhance alternative complement pathway activation on ECM, leading to increased C3 fragment deposition and C5b-9 formation.

Conclusions:

• FHR1 and FHR5 bind to novel ECM ligands, acting as competitive inhibitors of FH.
• Binding of FHR1 and FHR5 to ECM enhances local complement activation and promotes inflammation.
• These findings highlight a potential mechanism for FHR1 and FHR5 in driving pathological complement-mediated diseases.