C4b-binding protein binds to necrotic cells and DNA, limiting DNA release and inhibiting complement activation
Open Access
- 20 June 2005
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 201 (12), 1937-1948
- https://doi.org/10.1084/jem.20050189
Abstract
After cell death, via apoptosis or necrosis, the uptake of dead cells by neighboring cells or phagocytes prevents the release of intracellular content. An array of molecules, including initiation molecules of the complement system, are involved in marking dead cells for uptake. After binding of these molecules, complement activation takes place, which when uncontrolled might result in a proinflammatory state. In the current study we demonstrate that complement inhibitor, C4b-binding protein (C4BP), binds strongly to necrotic cells, irrespective of the cell type used or the method of induction. After binding of the C4BP–protein S (PS) complex to necrotic cells via PS-phosphatidylserine and C4BP-DNA interactions, C4BP-PS inhibits complement activation on these cells. C4BP binds DNA via a patch of positively charged amino acids, mainly on the second complement control domain of the C4BP α-chain (affinity constant: 190 nM). Furthermore, C4BP limits DNA release from necrotic cells and inhibits DNA-mediated complement activation in solution. The C4BP–necrotic cell interaction also occurs in vivo as necrotic areas of arteriosclerotic plaques and of various cancers stain strongly positive for C4BP. This study describes a novel mechanism in which C4BP limits the inflammatory potential of necrotic cells.This publication has 57 references indexed in Scilit:
- Nucleic Acid Is a Novel Ligand for Innate, Immune Pattern Recognition Collectins Surfactant Proteins A and D and Mannose-binding LectinPublished by Elsevier BV ,2004
- Quantification of Circulating DNA in the Plasma and Serum of Cancer PatientsAnnals of the New York Academy of Sciences, 2004
- Neutrophil Extracellular Traps Kill BacteriaScience, 2004
- A Cluster of Positively Charged Amino Acids in the C4BP α-Chain Is Crucial for C4b Binding and Factor I Cofactor FunctionOnline Journal of Public Health Informatics, 1999
- Soluble oligonucleosomal complexes in synovial fluid from inflamed jointsArthritis & Rheumatism, 1997
- CpG motifs in bacterial DNA trigger direct B-cell activationNature, 1995
- The Gene Coding for the β-Chain of C4b-Binding Protein (C4BPB) Has Become a Pseudogene in the MouseGenomics, 1994
- Complement deficiency and diseaseImmunology Today, 1991
- Serum amyloid P component is the major calcium-dependent specific DNA binding protein of the serumBiochemical and Biophysical Research Communications, 1987
- Fibronectin and C4-binding protein are selectively bound by aggregated amyloid P componentThe Journal of Experimental Medicine, 1981