Defining the Glycosaminoglycan Interactions of Complement Factor H-Related Protein 5

• Published in: The Journal of immunology (1950) 2021-07, Vol.207 (2), p.534-541
• Main Authors: Gyapon-Quast, Frederick, Goicoechea de Jorge, Elena, Malik, Talat, Wu, Nian, Yu, Jin, Chai, Wengang, Feizi, Ten, Liu, Yan, Pickering, Matthew C
• Format: Article
• Language: English
• Subjects: Complement Activation; Complement C3b; Complement Factor H; Glomerulonephritis, IGA; Glycosaminoglycans; Humans; Innate Immunity and Inflammation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000072

Complement activation is an important mediator of kidney injury in glomerulonephritis. Complement factor H (FH) and FH-related protein 5 (FHR-5) influence complement activation in C3 glomerulopathy and IgA nephropathy by differentially regulating glomerular complement. FH is a negative regulator of complement C3 activation. Conversely, FHR-5 in vitro promotes C3 activation either directly or by competing with FH for binding to complement C3b. The FH-C3b interaction is enhanced by surface glycosaminoglycans (GAGs) and the FH-GAG interaction is well-characterized. In contrast, the contributions of carbohydrates to the interaction of FHR-5 and C3b are unknown. Using plate-based and microarray technologies we demonstrate that FHR-5 interacts with sulfated GAGs and that this interaction is influenced by the pattern and degree of GAG sulfation. The FHR-5-GAG interaction that we identified has functional relevance as we could show that the ability of FHR-5 to prevent binding of FH to surface C3b is enhanced by surface kidney heparan sulfate. Our findings are important in understanding the molecular basis of the binding of FHR-5 to glomerular complement and the role of FHR-5 in complement-mediated glomerular disease.