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J. Biol. Chem., Vol. 279, Issue 49, 51250-51257, December 3, 2004

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SREC-I, a Type F Scavenger Receptor, Is an Endocytic Receptor for Calreticulin^*

Brent Berwin, Yves Delneste¶, Rachel V. Lovingood||, Steven R. Post**, and Salvatore V. Pizzo

From the Department of Pathology and ^||Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, ^¶Unité INSERM U564, University Hospital, Angers F49933, France, and ^**Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536

Calreticulin and gp96 (GRP94) traffic associated peptides into the major histocompatibility complex class-I cross-presentation pathway of antigen-presenting cells (APCs). Efficient accession of the cross-presentation pathway requires APC receptor-mediated endocytosis of the chaperone/peptide complexes. Previously, scavenger receptor class-A (SRA) was shown to play a substantial role in trafficking gp96 and calreticulin into macrophages, accounting for half of total receptor-mediated uptake. However, the scavenger receptor ligand fucoidin competed the chaperone uptake beyond that accounted for by SRA, indicating that another scavenger receptor(s) may also contribute. Consistent with this hypothesis, we showed that the residual calreticulin uptake into SRA^-/- macrophages is competed by the scavenger receptor ligand acetylatedlow density lipoprotein (LDL). We now report that an additional scavenger receptor, SREC-I (scavenger receptor expressed by endothelial cell-I), mediates the endocytosis of calreticulin and gp96. Ectopic expression of SREC-I in Chinese hamster ovary cells yielded chaperone recognition and uptake, and these processes were competed by the inhibitory ligands fucoidin and acetylated (Ac)LDL. Although AcLDL competes for the chaperone interactions with SRA and SREC, we showed that not all of the scavenger receptors, which bind AcLDL, bind calreticulin or gp96. The overexpression of SREC-I in macrophages increased chaperone endocytosis, indicating that SREC-I functions in APCs and that the cytosolic components necessary for the endocytosis of SREC-I and its cargo are present and not limiting in APCs. These data identify a novel class of ligands for SREC-I and provide insight into the mechanisms by which APCs and potentially endothelial cells traffic chaperone/antigen complexes.

Received for publication, June 3, 2004 , and in revised form, August 5, 2004.

^* This work was supported by Grants HL-24066 (to S. V. P.), HL-68072 (to J. R. Wright), and National Research Service Award 1F32CA9016901 (to B. B.). 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.

Present address: Dept. of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756.

To whom correspondence should be addressed. Tel.: 919-684-3528; Fax: 919-684-8689; E-mail: pizzo001{at}mc.duke.edu.

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