Alternative titles; symbols
HGNC Approved Gene Symbol: CLEC5A
Cytogenetic location: 7q34 Genomic coordinates (GRCh38): 7:141,927,357-141,946,974 (from NCBI)
CLEC5A is a type II transmembrane protein with a short cytoplasmic tail. It requires association with the adaptor protein DAP12 (TYROBP; 604142) to initiate signaling (summary by Wortham et al., 2016).
Crosslinking of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptor complexes on a variety of cells leads to their activation through the sequential triggering of protein tyrosine kinases. DAP12 is an ITAM-bearing signaling molecule that is noncovalently associated with activating isoforms of MHC class I receptors on natural killer cells. In addition to natural killer cells, DAP12 is expressed in peripheral blood monocytes, macrophages, and dendritic cells, suggesting association with other receptors present in these cell types. Using an indirect expression cloning strategy to identify mouse Dap12-associating molecules expressed in myeloid cells, Bakker et al. (1999) isolated mouse cDNAs encoding Clecsf5, which they called Mdl1. The predicted Clecsf5 protein is a type II transmembrane protein consisting of a short, 2-amino acid intracellular region, a transmembrane domain containing a positively charged amino acid that enables it to pair with Dap12, and an extracellular domain containing characteristic structural motifs of the C-type lectin superfamily. Database searches revealed a mouse EST encoding a Clecsf5 isoform containing an additional 25 amino acids in the extracellular region proximal to the transmembrane domain. In addition, it contains an extra putative N-linked glycosylation site. The authors identified a human EST encoding CLECSF5. Human CLECSF5, which contains 187 amino acids, shares 69% amino acid sequence identity with the long isoform of mouse Clecsf5. PCR analysis of a panel of human cDNAs detected CLECSF5 expression in normal peripheral blood monocytes and in 2 monocyte/macrophage cell lines, but not in cell lines of other origins.
By FISH, Bakker et al. (1999) mapped the CLECSF5 gene to chromosome 7q33.
Bakker et al. (1999) demonstrated that recombinant human CLECSF5 selectively associated with mouse Dap12. Crosslinking of CLECSF5 and Dap12 in mouse macrophage cells resulted in calcium mobilization. Bakker et al. (1999) suggested that signaling via CLECSF5/DAP12 complexes may constitute a significant activation pathway in myeloid cells.
Using ELISA, Chen et al. (2008) found that CLEC5A, in addition to DCSIGN (CD209; 604672), interacted with dengue virus (DV; see 614371). The DV-CLEC5A interaction promoted phosphorylation of DAP12 and did not result in viral entry, but it did stimulate secretion of proinflammatory cytokines, including TNF (191160) and IL6 (147620), by macrophages. Blockade of DV-CLEC5A interaction suppressed proinflammatory cytokine secretion without affecting IFNA (147660) release. Treatment of DV-infected Stat1 (600555)-deficient mice with anti-Clec5a inhibited DV-induced plasma leakage and subcutaneous and vital organ hemorrhaging, resulting in a 50% reduction in mortality. Chen et al. (2008) proposed that CLEC5A signaling blockade offers a promising strategy for mitigating the effects of dengue hemorrhagic fever and dengue shock syndrome.
By quantitative PCR of human and mouse tissues, Joyce-Shaikh et al. (2010) detected highest expression of MDL1 in bone marrow cells and joints. In tissue from patients with rheumatoid arthritis (180300) and in mouse inflamed joint, MDL1 was highly expressed on myeloid cells in the inflamed panus. Mdl1 activation enhanced recruitment of inflammatory macrophages and neutrophils to joints and promoted bone erosion in mice. Deletion of Mdl1 or treatment with an Mdl1-Ig fusion protein in mice reduced autoimmune joint inflammation. Joyce-Shaikh et al. (2010) proposed that MDL1 may be a therapeutic target for immune-mediated skeletal disorders.
Wortham et al. (2016) observed Clec5a expression on alveolar macrophages in mice exposed long term to cigarette smoke (CS), a model of chronic obstructive pulmonary disease (COPD; see 606963), as well as in human smokers. Using Clec5a-deficient mice, they showed that Clec5a expression was required for development of CS-induced macrophage responsiveness, cytokine production, pulmonary inflammation, macrophage activation, and lung remodeling. Wortham et al. (2016) proposed that CLEC5A is a potential target for therapeutic inhibition of aberrant macrophage activation in COPD pathogenesis.
Bakker, A. B. H., Baker, E., Sutherland, G. R., Phillips, J. H., Lanier, L. L. Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells. Proc. Nat. Acad. Sci. 96: 9792-9796, 1999. [PubMed: 10449773] [Full Text: https://doi.org/10.1073/pnas.96.17.9792]
Chen, S.-T., Lin, Y.-L., Huang, M.-T., Wu, M.-F., Cheng, S.-C., Lei, H.-Y., Lee, C.-K., Chiou, T.-W., Wong, C.-H., Hsieh, S.-L. CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453: 672-676, 2008. [PubMed: 18496526] [Full Text: https://doi.org/10.1038/nature07013]
Joyce-Shaikh, B., Bigler, M. E., Chao, C.-C., Murphy, E. E., Blumenschein, W. M., Adamopoulos, I. E., Heyworth, P. G., Antonenko,S., Bowman, E. P., McClanahan, T. K., Phillips, J. H., Cua, D. J. Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis. J. Exp. Med. 207: 579-589, 2010. [PubMed: 20212065] [Full Text: https://doi.org/10.1084/jem.20090516]
Wortham, B. W., Eppert, B. L., Flury, J. L., Garcia, S. M., Donica, W. R., Osterburg, A., Joyce-Shaikh, B., Cua, D. J., Borchers, M. T. Cutting edge: CLEC5A mediates macrophage function and chronic obstructive pulmonary disease pathologies. J. Immun. 196: 3227-3231, 2016. [PubMed: 26927798] [Full Text: https://doi.org/10.4049/jimmunol.1500978]