Alternative titles; symbols
HGNC Approved Gene Symbol: SCARF1
Cytogenetic location: 17p13.3 Genomic coordinates (GRCh38): 17:1,633,858-1,645,732 (from NCBI)
Scavenger receptors mediate the endocytosis of chemically modified lipoproteins. SCARF1 specifically mediates the selective uptake of acetylated low density lipoprotein (Ac-LDL) into endothelial cells.
By sequencing clones obtained from a myeloid leukemia cell cDNA library, Nagase et al. (1995) cloned SCARF1, which they designated KIAA0149. The deduced 830-amino acid protein contains a putative transmembrane domain and an EGF-like pattern of cysteine repeats. SCARF1 shares about 33% identity over 147 amino acids with mouse Tie2 (600221), an epithelial receptor tyrosine kinase. The 3-prime untranslated region contains an Alu repeat. Northern blot analysis detected expression in most tissues examined, with highest levels in lung and spleen. No expression was detected in HeLa cells, pancreas, or colon.
Adachi et al. (1997) cloned SCARF1, which they designated SREC, using an expression cloning strategy in which they assayed for uptake of fluorescence-labeled Ac-LDL into CHO cells transfected with a human umbilical vein endothelial cell (HUVEC) cDNA library. The deduced 830-amino acid protein has a calculated molecular mass of about 86 kD. SCARF1 contains a hydrophobic signal sequence followed by 5 EGF-like cysteine pattern signatures in its extracellular N-terminal half, a transmembrane region, and an intracellular C-terminal half containing a serine/proline-rich region followed by a glycine-rich region. It has 3 potential N-glycosylation sites and several putative sites for serine and threonine phosphorylation. Northern blot analysis revealed a 3.5-kb transcript expressed in HUVECs and in coronary artery endothelial cells, but not in coronary artery smooth muscle cells.
Adachi and Tsujimoto (2002) identified several SCARF1 variants in a peripheral blood leukocyte cDNA library. Alternative splicing introduces a stop codon before the transmembrane region in 2 of the variants, resulting in soluble forms of SCARF1.
Adachi et al. (1997) determined that CHO cells stably expressing SCARF1 bound radiolabeled Ac-LDL with high affinity and degraded it via an endocytic pathway. The association between SCARF1 and Ac-LDL was inhibited by oxidized LDL, malondialdehyde-modified LDL, dextran sulfate, and polyinosinic acid, but not by natural LDL or heparin.
Adachi and Tsujimoto (2002) determined that all membrane-bound splice variants of SCARF1 showed receptor activity toward Ac-LDL. They identified a transcriptional activator of SCARF1, ZNF444 (607874). Overexpression of ZNF444 in HUVECs increased SCARF1 promoter activity nearly 2.5-fold. An intact SP1 (189906) motif and an intact inverted repeat sequence with a triple-nucleotide spacer (IR3), which binds ZNF444, were required for maximal SCARF1 expression. Several inflammatory cytokines inhibited SCARF1 promoter activity in vitro and decreased Ac-LDL uptake in vivo.
Means et al. (2009) showed that the scavenger receptors Scarf1 and Cd36 (173510) mediated mouse defense against 2 fungal pathogens, Cryptococcus neoformans and Candida albicans, by enabling production of antimicrobial peptides. Studies in C. elegans indicated that the homologous proteins protected nematodes. Macrophage binding and cytokine production required Cd36, but not Tlr2 (603028), and binding was dependent on recognition of pathogen beta-glucans. Mice lacking Cd36, but expressing other beta-glucan receptors (e.g., CLEC7A; 606264), had a higher fungal burden and greater mortality after intravenous infection with C. neoformans compared with wildtype mice. Means et al. (2009) concluded that SCARF1 and CD36 are beta-glucan-binding receptors and are involved in an evolutionarily conserved pathway for the innate sensing of fungal pathogens.
Adachi and Tsujimoto (2002) determined that the SCARF1 gene contains 11 exons and spans 12 kb. The 5-prime flanking region lacks TATA and CCAAT boxes, but it contains several putative motifs for DNA-binding elements, including an SP1 motif and an IR3 sequence that binds ZNF444.
By PCR of a human/rodent hybrid panel, Nagase et al. (1995) mapped the SCARF1 gene to chromosome 17.
Adachi, H., Tsujimoto, M. Characterization of the human gene encoding the scavenger receptor expressed by endothelial cell and its regulation by a novel transcription factor, endothelial zinc finger protein-2. J. Biol. Chem. 277: 24014-24021, 2002. [PubMed: 11978792] [Full Text: https://doi.org/10.1074/jbc.M201854200]
Adachi, H., Tsujimoto, M., Arai, H., Inoue, K. Expression cloning of a novel scavenger receptor from human endothelial cells. J. Biol. Chem. 272: 31217-31220, 1997. [PubMed: 9395444] [Full Text: https://doi.org/10.1074/jbc.272.50.31217]
Means, T. K., Mylonakis, E., Tampakakis, E., Colvin, R. A., Seung, E., Puckett, L., Tai, M. F., Stewart, C. R., Pukkila-Worley, R., Hickman, S. E., Moore, K. J., Calderwood, S. B., Hacohen, N., Luster, A. D., El Khoury, J. Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36. J. Exp. Med. 206: 637-653, 2009. [PubMed: 19237602] [Full Text: https://doi.org/10.1084/jem.20082109]
Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., Nomura, N. Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995. [PubMed: 8590280] [Full Text: https://doi.org/10.1093/dnares/2.4.167]