title: SREC-I, a type F scavenger receptor, is an endocytic receptor for calreticulin.
abstract: 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 acetylated low 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.
authors.affiliation: Department of Pathology and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Brent
authors.initials: B
authors.lastname: Berwin
authors.forename: Yves
authors.initials: Y
authors.lastname: Delneste
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Lovingood
authors.forename: Steven R
authors.initials: SR
authors.lastname: Post
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Pizzo
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016466:CHO Cells; D037282:Calreticulin / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000502:physiology*; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D005456:Fluorescent Dyes / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D008024:Ligands; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000737:chemistry / Q000502:physiology*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051128:Scavenger Receptors, Class F; D014162:Transfection
chemical_list: D037282:Calreticulin; D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; D005456:Fluorescent Dyes; D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D018832:Molecular Chaperones; D010455:Peptides; D011134:Polysaccharides; D020033:Protein Isoforms; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051128:Scavenger Receptors, Class F; C018551:glucose-regulated proteins; C007789:fucoidan