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J. Biol. Chem., Vol. 280, Issue 42, 35733-35741, October 21, 2005

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Histidine-rich Glycoprotein Specifically Binds to Necrotic Cells via Its Amino-terminal Domain and Facilitates Necrotic Cell Phagocytosis^*

Allison L. Jones, Ivan K. H. Poon, Mark D. Hulett1, and Christopher R. Parish2

From the Cancer and Vascular Biology Group, Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, 0200, Australia and the Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Box 582, S-751 23 Uppsala, Sweden

Cells that become necrotic or apoptotic through tissue damage or during normal cellular turnover are usually rapidly cleared from the circulation and tissues by phagocytic cells. A number of soluble proteins have been identified that facilitate the phagocytosis of apoptotic cells, but few proteins have been defined that selectively opsonize necrotic cells. Previous studies have shown that histidine-rich glycoprotein (HRG), an abundant (100 µg/ml) 75-kDa plasma glycoprotein, binds to cell surface heparan sulfate on viable cells and cross-links other ligands, such as plasminogen, to the cell surface. In this study we have demonstrated that HRG also binds very strongly, in a heparan sulfate-independent manner, to cytoplasmic ligand(s) exposed in necrotic cells. This interaction is mediated by the amino-terminal domain of HRG and results in enhanced phagocytosis of the necrotic cells by a monocytic cell line. In contrast, it was found that HRG binds poorly to and does not opsonize early stage apoptotic cells. Thus, HRG has the unique property of selectively recognizing necrotic cells and may play an important physiological role in vivo by facilitating the uptake and clearance of necrotic, but not apoptotic, cells by phagocytes.

Received for publication, April 21, 2005 , and in revised form, July 22, 2005.

^* This work was supported in part by a National Health and Medical Research Council program grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Viertel Senior Medical Research fellowship.

² To whom correspondence should be addressed: Division of Immunology and Genetics, John Curtin School of Medical Research, Bldg. 54, Mills Rd., Australian National University, Canberra, Australian Capital Territory, 0200, Australia. Tel.: 61-2-61252604; Fax: 61-2-61252595; E-mail: christopher.parish{at}anu.edu.au.

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