The complement protein properdin recognizes glycosaminoglycan chains on apoptotic and malignant cell surfaces

Abstract

The complement alternative pathway (AP) C3 convertase, a central player of the complement cascade, tags potential targets with C3 fragments that in turn direct lysis and/or clearance and inflammatory reactions. The complement protein properdin has long been known to stabilize the AP convertase. Recently we have found that properdin is also a danger‐recognition molecule: Properdin can bind malignant and apoptotic cells and certain pathogenic microbes. Once bound to a surface, properdin provides a platform for the assembly of the AP C3 convertase, leading to opsonization and clearance and/or lysis. We are interested the mechanism by which properdin can recognize such a variety of potential targets.Properdin is composed of 6 thrombospondin repeats, which in other proteins can harbor glycosaminoglycan (GAG) binding sites. Thus, we investigated the possibility that properdin attaches to mammalian cells via GAGs. Using a panel of wild type and mutant CHO lines, we observed that properdin can bind cells via heparin sulfate and chondroitin sulfate GAG chains associated with cell surface proteoglycans. We then examined properdin interactions with human cells and found that properdin binds GAGs on apoptotic and malignant cell surfaces. Experiments with soluble GAG competitors suggest that properdin harbors multiple GAG‐binding sites that differ in GAG specificity. Supported by NIHR01AI05143.