Alternative titles; symbols
HGNC Approved Gene Symbol: MRC1
Cytogenetic location: 10p12.33 Genomic coordinates (GRCh38) : 10:17,809,348-17,911,164 (from NCBI)
Recognition of complex carbohydrate structures plays an important role in a number of biologic processes, including cell-cell recognition, serum glycoprotein turnover, and neutralization of pathogens (Kim et al., 1992). Many of the endogenous animal lectins that mediate these recognition events share a common Ca(2+)-dependent structural motif that has been designated a C-type carbohydrate-recognition domain (CRD). The mannose receptor found on macrophages and on endothelial cells of the liver is the only known example of a C-type lectin that contains multiple C-type CRDs. One function of the receptor is to bind high-mannose structures on the surface of potentially pathogenic viruses, bacteria, and fungi, so that they can be neutralized by phagocytic engulfment.
Kim et al. (1992) characterized the gene for the human macrophage mannose receptor (MRC1) by isolation of clones covering the entire coding region. MRC1 was demonstrated to be divided into 30 exons. The first 3 exons encode the signal sequence, the NH2-terminal cysteine-rich domain, and the fibronectin type II repeat, while the final exon encodes the transmembrane anchor and the cytoplasmic tail. The intervening 26 exons encode the 8 carbohydrate-recognition domains and intervening spacer elements.
By fluorescence in situ hybridization and PCR-based somatic cell hybrid mapping, Eichbaum et al. (1994) assigned the MRC1 gene to 10p13. Harris et al. (1994) mapped the mouse homolog, Mrc1, to chromosome 2. This region of the mouse genome contains at least 5 loci that are known to be on human 10p11-q15.
Nguyen and Hildreth (2003) showed that MMR mediated the initial association of human immunodeficiency virus (HIV; see 609423) with macrophages lacking expression of DCSIGN (CD209; 604672). Virus uptake and transmission from macrophages to T cells could be blocked by mannan, mannose, and mannose-binding lectin, but not by galactose. Cells lacking MMR were not inhibited by these agents. Nguyen and Hildreth (2003) concluded that MMR has a substantial role in binding and transmission of HIV-1 by macrophages.
Lefevre et al. (2013) observed increased mRNA and protein expression for the C-lectin receptors dectin-1 (CLEC7A; 606264), Mr, and Signr3, a mouse homolog of CD209, in mice infected with Leishmania infantum (Li) (see 608207). Mice lacking dectin-1 or Mr, but not those lacking Signr3, had higher parasite levels in blood and spleen. Peritoneal macrophages from dectin-1 -/- or Mrc1 -/- mice, but not Signr3 -/- mice, permitted Li growth and exhibited poor production of reactive oxygen species (ROS). ROS production required dectin-1-Syk (600085)-p47-phox (NCF1; 608512) phosphorylation and Mr-arachidonic acid-Nadph oxidase (NOX1; 300225) membrane translocation. Dectin-1 and Mr facilitated release of Il1b (147720) induced by Casp1 (147678) in response to Li infection, whereas Il1b was downregulated by Signr3 through Lta4h (151570). In human macrophages, small interfering RNA-mediated inactivation of CLEC7A and MRC1, but not CD209, resulted in responses to Li similar to those observed in mice. Lefevre et al. (2013) concluded that Leishmania-macrophage interaction is influenced by the stage of macrophage polarization (i.e., by cytokine and stimulatory milieu) and by members of the C-lectin receptor family. They proposed that alteration of these cellular and molecular factors may benefit patient responses.
By analyzing non-synonymous SNPs in exon 7 of MRC1, Alter et al. (2010) determined that only G396S (rs1926736) is polymorphic in the Vietnamese population. Testing 704 leprosy patients (325 paucibacillary and 374 multibacillary) from 490 simplex and 90 multiplex families showed that S396 is protective against both leprosy per se and multibacillary leprosy. Follow-up analysis in 384 Brazilian leprosy patients and 399 controls found additional exon 7 polymorphisms but again indicated that susceptibility to leprosy per se and multibacillary leprosy is significantly associated with G396. Functional analysis of an embryonic kidney cell line overexpressing the mannose receptor with 3 exon 7 haplotypes of MRC1 found no differences in uptake of ovalbumin or fucose ligands and none of the constructs were able to bind and internalize viable Mycobacterium leprae or bacille Calmette-Guerin (BCG). Alter et al. (2010) proposed that interaction between MRC1 and M. leprae is modulated by an unknown host molecule.
Lee et al. (2002) generated mice genetically deficient in mannose receptor. MR -/- mice were defective in clearing proteins bearing accessible mannose and N-acetylglucosamine residues and had elevated levels of 8 different lysosomal hydrolases. Proteomic analysis of MR -/- and control mouse sera showed that an additional 4 out of 52 proteins identified were elevated in MR -/- serum. Each of these proteins is upregulated during inflammation and wound healing. Thus, Lee et al. (2002) concluded that MR appears to operate as an essential regulator of serum glycoprotein homeostasis. The proteins upregulated during inflammation included C-terminal propeptide domains of the pro-alpha-1 and -2 chains of type I procollagen (120150 and 120160, respectively) and the pro-alpha-1 chain of type III procollagen (120180), as well as fetuin-B (605954). Lee et al. (2002) demonstrated that the mannose receptor is required for rapid clearance of a subset of mannose-bearing serum glycoproteins that are normally elevated during inflammation, but it does not appear to regulate the initiation of inflammation.
Using Mr-deficient mice, Burgdorf et al. (2007) showed that dendritic cells and macrophages used only Mr-mediated endocytosis to obtain antigen for Cd8 (see 186910)-positive T-cell activation, whereas pinocytosis and, in the case of macrophages, scavenger receptors (see MSR1; 153622) were used for Cd4 (186940)-positive T-cell activation. Fluorescence microscopy demonstrated that Mr-mediated endocytosis supplied an early endosomal compartment containing Rab5 (179512) and Eea1 (605070) that was distinct from the lysosomes supplied by scavenger receptors and pinocytosis. Burgdorf et al. (2007) proposed that targeting antigen to MR may be an avenue for improving vaccines aimed at inducing CD8-positive T cell-mediated immunity to viruses or tumors.
By testing for exon 7 polymorphisms in Vietnamese and Brazilian leprosy patients and family or healthy controls, Alter et al. (2010) determined that susceptibility to leprosy per se and to multibacillary leprosy is significantly associated with Gly at position 396, resulting from the G-to-A substitution in the first position of the codon.
Alter, A., de Leseleuc, L., Van Thuc, N., Thai, V. H., Huong, N. T., Ba, N. N., Cardoso, C. C., Grant, A. V., Abel, L., Moraes, M. O., Alcais, A., Schurr, E. Genetic and functional analysis of common MCR1 exon 7 polymorphisms in leprosy susceptibility. Hum. Genet. 127: 337-348, 2010. [PubMed: 20035344] [Full Text: https://doi.org/10.1007/s00439-009-0775-x]
Burgdorf, S., Kautz, A., Bohnert, V., Knolle, P. A., Kurts, C. Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science 316: 612-616, 2007. [PubMed: 17463291] [Full Text: https://doi.org/10.1126/science.1137971]
Eichbaum, Q., Clerc, P., Bruns, G., McKeon, F., Ezekowitz, R. A. B. Assignment of the human macrophage mannose receptor gene (MRC1) to 10p13 by in situ hybridization and PCR-based somatic cell hybrid mapping. Genomics 22: 656-658, 1994. [PubMed: 8001982] [Full Text: https://doi.org/10.1006/geno.1994.1445]
Harris, N., Peters, L. L., Eicher, E. M., Rits, M., Raspberry, D., Eichbaum, Q. G., Super, M., Ezekowitz, R. A. B. The exon-intron structure and chromosomal localization of the mouse macrophage mannose receptor gene, Mrc1: identification of a ricin-like domain at the N-terminus of the receptor. Biochem. Biophys. Res. Commun. 198: 682-692, 1994. [PubMed: 8297379] [Full Text: https://doi.org/10.1006/bbrc.1994.1099]
Kim, S. J., Ruiz, N., Bezouska, K., Drickamer, K. Organization of the gene encoding the human macrophage mannose receptor (MRC1). Genomics 14: 721-727, 1992. [PubMed: 1294118] [Full Text: https://doi.org/10.1016/s0888-7543(05)80174-0]
Lee, S. J., Evers, S., Roeder, D., Parlow, A. F., Risteli, J., Risteli, L., Lee, Y. C., Feizi, T., Langen, H., Nussenzweig, M. C. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295: 1898-1901, 2002. [PubMed: 11884756] [Full Text: https://doi.org/10.1126/science.1069540]
Lefevre, L., Lugo-Villarino, G., Meunier, E., Valentin, A., Olagnier, D., Authier, H., Duval, C., Dardenne, C., Bernad, J., Lemesre, J. L., Auwerx, J., Neyrolles, O., Pipy, B., Coste, A. The C-type lectin receptors Dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum. Immunity 38: 1038-1049, 2013. [PubMed: 23684988] [Full Text: https://doi.org/10.1016/j.immuni.2013.04.010]
Nguyen, D. G., Hildreth, J. E. K. Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages. Europ. J. Immun. 33: 483-493, 2003. [PubMed: 12645947] [Full Text: https://doi.org/10.1002/immu.200310024]