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To the Surface of Apoptotic Cells Complement Regulator C4b Vitamin K-Dependent Protein S Localizing Complement Regulator C4b-Binding Protein to the Surface of Apoptotic Cells This information is current as Joanna H. Webb, Anna M. Blom and Björn Dahlbäck of September 27, 2021. J Immunol 2002; 169:2580-2586; ; doi: 10.4049/jimmunol.169.5.2580 http://www.jimmunol.org/content/169/5/2580 Downloaded from References This article cites 67 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/169/5/2580.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Vitamin K-Dependent Protein S Localizing Complement Regulator C4b-Binding Protein to the Surface of Apoptotic Cells1 Joanna H. Webb, Anna M. Blom, and Bjo¨rn Dahlba¨ck2 Apoptosis is characterized by a lack of inflammatory reaction in surrounding tissues, suggesting local control of complement activation. During the initial stage of apoptosis, cells expose negatively charged phospholipid phosphatidylserine on their surfaces. The vitamin K-dependent protein S has a high affinity for this type of phospholipid. In human plasma, 60–70% of protein S circulates in complex with C4b-binding protein (C4BP). The reason why protein S and C4BP form a high-affinity complex in plasma is not known. However, C4BP is an important regulator of the classical pathway of the complement system where it acts as a cofactor in degradation of complement protein C4b. Using Jurkat cells as a model system for apoptosis, we now show protein Downloaded from S to bind to apoptotic cells. We further demonstrate protein S-mediated binding of C4BP to apoptotic cells. Binding of the C4BP-protein S complex to apoptotic cells was calcium-dependent and could be blocked with Abs directed against the phospho- lipid-binding domain in protein S. Annexin V, which binds to exposed phosphatidylserine on the apoptotic cell surface, could inhibit the binding of protein S. The C4BP that was bound via protein S to the apoptotic cells was able to interact with the complement protein C4b, supporting a physiological role of the C4BP/protein S complex in regulation of complement on the surface of apoptotic cells. The Journal of Immunology, 2002, 169: 2580–2586. http://www.jimmunol.org/ poptosis is under physiological conditions a well-regu- charged phospholipids, e.g., activated protein C (apc)3 and protein lated process, characterized by a lack of induction of S (16). Protein S functions as cofactor to apc in the degradation of A inflammatory responses in the surrounding tissue (1). In factors Va and VIIIa (17, 18). The importance of protein C and viable cells, an asymmetric distribution of phospholipids between protein S is demonstrated by the fact that deficiency of either is the outer and inner leaflet of the membrane is maintained, the associated with increased risk of thrombosis (19, 20). Because an- negatively charged phosphatidylserine being predominantly local- ionic membrane surfaces (such as that provided by activated plate- ized in the inner leaflet (2). Erythrocytes and platelets were the first lets) have been shown to be equally competent in promoting pro- cells where this asymmetry was described (3, 4), but it was later and anticoagulant reactions (21, 22), it is likely that the surface of by guest on September 27, 2021 also found to be true for nucleated cells (5). During one of the first apoptotic cells is also able to promote anticoagulant reactions. stages of apoptosis, phosphatidylserine is transferred from the in- In plasma, protein S exists in two forms; ϳ30–40% circulates ner leaflet of the cell membrane to the outer leaflet (6, 7), resulting as free protein S, the remainder forming a 1:1 high-affinity (Kd in in the exposure of negatively charged phospholipid on the cell a range of 0.1–0.6 nM) complex with C4b-binding protein (C4BP; surface. This has been suggested to be a phagocytosis-stimulating Refs. 23–26). Only free protein S works as a cofactor to apc (27). signal to neighboring cells, resulting in the elimination of the ap- Protein S contains multiple domains, including an N-terminal optotic cell remnants. ␥-carboxy glutamic acid (Gla)-rich domain, which binds Ca2ϩ and Negatively charged phospholipid membranes, e.g., exposed on is responsible for the interaction with negatively charged phospho- activated platelets, bind vitamin K-dependent coagulation factors, lipids, a thrombin sensitive region, four epidermal growth factor thus supporting the assembly of procoagulant enzyme-cofactor (EGF)-like domains, and two laminin G-type domains. The G do- complexes (8–12). Several studies have also shown apoptotic cells mains are involved in the interaction with C4BP, especially resi- to have procoagulant properties (13–15). However, there are also dues 605–614 (28, 29), 420–434 (30, 31), and 447–460 (32). anticoagulant vitamin K-dependent proteins that bind negatively C4BP is an important regulator of the classical pathway of com- plement. It functions as a cofactor to factor I in the degradation of C4b (33). Furthermore, it inhibits the formation of the C3 conver- Division of Clinical Chemistry, Department of Laboratory Medicine, University Hos- tase (formed by C4b and C2a) and accelerates its decay (34). The pital Malmo¨, Lund University, Malmo¨, Sweden structure of C4BP resembles that of an octopus. It consists of seven Received for publication April 4, 2002. Accepted for publication June 19, 2002. identical ␣-chains, and one unique ␤-chain, the chains being held The costs of publication of this article were defrayed in part by the payment of page together in a central core. Several complement control protein charges. This article must therefore be hereby marked advertisement in accordance ␣ with 18 U.S.C. Section 1734 solely to indicate this fact. (CCP) modules compose each chain, the -chains having eight CCPs and the ␤-chain having three. Each ␣-chain binds a C4b, and 1 This work was supported by grants from the Swedish Research Council (07143), a Senior Investigator Award from the Swedish Foundation for Strategic Research, the a positively charged area on the interface between CCP1 and 2 is Cancer Foundation, the Network for Inflammation Research funded by the Swedish important for the binding (35). The ␤-chain binds protein S, the Foundation for Strategic Research, the Tore Nilson’s Trust, the Crafoord trust, the O¨ sterlunds Trust, Greta and Johan Kock’s Trust, and research funds from the Uni- main binding site being localized to CCP1 and involving a large versity Hospital Malmo¨. 2 Address correspondence and reprint requests to Dr. Bjo¨rn Dahlba¨ck, Division of Clinical Chemistry, Department of Laboratory Medicine, University Hospital Malmo¨, 3 Abbreviations used in this paper: apc, activated protein C; C4BP, C4b-binding pro- Lund University, S-205 02 Malmo¨, Sweden. E-mail address: Bjorn.Dahlback@ tein; CCP, complement control protein; 7-AAD, 7-amino actinomycin D; SAP, serum klkemi.mas.lu.se amyloid P component; EGF, epidermal growth factor; Gla, ␥-carboxy glutamic acid. Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 The Journal of Immunology 2581 hydrophobic patch (36, 37). CCP2 also seems to contribute slightly measuring absorbance at 495 nm. Rates of FITC to protein were within to the interaction (38). recommended range (0.3–1.0; Ref. 51). The physiological role of the complex between C4BP and pro- Binding experiments tein S has remained an enigma. It has been suggested that protein ␮ S, due to its high affinity for negatively charged phospholipids, A total of 75 l of cells were incubated with protein S, C4BP, plasma purified C4BP/protein S complex, or protein S preincubated with C4BP (at localizes C4BP to areas where such phospholipids are exposed 37°C for 30 min, in the presence of 2 mM CaCl2) in binding buffer in a final (39). The complex binds to synthetic phospholipid vesicles, but not volume of 100 ␮l. In time course studies, binding of protein S leveled of to platelet-derived microparticles, even though free protein S ef- at 25 min at room temperature, and remained stable at least until 60 min ficiently binds to these particles (40). (data not shown). Therefore, 25 min was chosen as incubation time. Cells ϫ It has been demonstrated that complement components attach to were then pelleted by centrifugation for 2 min at 350 g, and washed in binding buffer. Following a second centrifugation, 15 ␮g/ml FITC-labeled apoptotic cells, C1 arguably being the most important. C1q defi- Abs, HPS 54 for protein S, and MK 104 for all protein containing C4BP, ciency may predispose to autoimmunity in systemic lupus ery- annexin V labeled with PE (annexin V-PE; BD Biosciences, Mountain thematosus as a consequence of an impaired clearance of apoptotic View, CA), 5 ␮l10ϫ diluted, and 5 ␮l 7-amino actinomycin D (7-AAD; cells (41–44). Binding of C1 to apoptotic cells could result in ViaProbe; BD Biosciences) were added in binding buffer at a final volume of 100 ␮l.
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