Disease relevance of CD93

• Human antibodies from Sjögren's syndrome patients did not recognize C1qR, but showed positive reaction with the purified 53,000 MW component from spleen [1].
• We now investigated whether Escherichia coli possesses a C1qR-like protein that protects these bacteria from complement-mediated injury [2].
• We have previously demonstrated that hepatitis C virus (HCV) core, the first protein to be expressed and circulating in the blood of infected individuals, inhibited human T cell proliferative response through interaction with the complement receptor, globular domain of C1q receptor (gC1qR) [3].
• The HD-increased C1qR that binds C1q to the surface of HEK might be a contributing mechanism or a marker for the inflammation and vesication associated with HD exposure [4].

High impact information on CD93

• Likewise, C1-Inh leads to C1q remaining on the immune complex to interact with the C1q receptor [5].
• Thus, CR1 is a cellular C1q receptor that recognizes all three complement opsonins, namely, C1q, C3b, and C4b [6].
• Mannose binding protein (MBP) enhances mononuclear phagocyte function via a receptor that contains the 126,000 M(r) component of the C1q receptor [7].
• C1q receptors (C1qR) have been identified on a variety of somatic and cultured cells including peripheral blood platelets [8].
• Platelet aggregation was inhibited by the collagenous domain of C1q (c-Clq) and a monoclonal antibody directed against C1q receptors, suggesting the direct involvement of the 67-kD platelet C1qR [8].

Biological context of CD93

• Recent studies using mice deficient in CD93 have demonstrated that this molecule modulates phagocytosis of apoptotic cells in vivo [9].
• Metabolic labeling studies show that when glycosylation is absent, C1qRP/CD93 is synthesized and rapidly released into the culture supernatant or degraded [10].
• To investigate signal transduction mechanisms mediated by CD93, CD93 cytoplasmic tail (CYTO)-binding proteins were identified in a yeast two-hybrid screen [9].
• Using the yeast two-hybrid system and an in vitro glutathione S-transferase fusion protein-binding assay, the binding of GIPC to the CYTO was shown to involve a newly identified class I PDZ-binding domain in the CD93 carboxyl terminus [9].
• The C1q and collectin binding site within C1q receptor (cell surface calreticulin) [11].

Anatomical context of CD93

• Treatment of human monocytes with a cell-permeable peptide encoding the C-terminal 11 amino acids of CD93 resulted in an enhancement of phagocytosis, supporting the hypothesis that this protein-protein interaction domain is involved in the modulation of phagocytosis [9].
• CD93 is a approximately 120 kDa O-sialoglycoprotein that within the hematopoietic system is selectively expressed on cells of the myeloid lineage [12].
• A C1q receptor that upregulates the phagocytic capacity of professional phagocytes, C1qRp, has been identified, and its primary structure determined by cDNA cloning and sequencing [13].
• The Ca2+ storage protein calreticulin is associated with the endoplasmic reticulum and shares a high degree of amino acid homology with the surface receptor C1q-R [14].
• Western blots of neutrophil subcellular fractions located calreticulin in both the cytosol and cell membrane fractions; C1q-R was largely confined to the cell membrane [14].

Associations of CD93 with chemical compounds

• While the cDNA for C1qRP encodes a 631 amino acid membrane protein, Chinese hamster ovary cells transfected with the cDNA of the C1qRP coding region express a surface glycoprotein with the identical 126,000 Mr in SDS-PAGE as the native C1qRP [15].
• Furthermore, no supporting evidence for a role of CD93 as an adhesion molecule was found using intravital microscopy or analyzing peritoneal cell recruitment in response to three different inflammatory stimuli (thioglycolate, zymosan A, and IL-1beta) [16].
• Whereas recombinant tumor necrosis factor-alpha (rTNF-alpha) slightly up-regulated CD93 expression on the U937 cells, recombinant interleukin-1beta (rIL-1beta), recombinant interleukin-2 (rIL-2), recombinant interferon-gamma (rIFN-gamma) and lipopolysaccharide (LPS) had no effect [17].
• CD93 expression was analyzed using flow cytometry and glutaraldehyde-fixed cellular enzyme-linked immunoassay (EIA) techniques utilizing a CD93 monoclonal antibody (mAb), mNI-11, that was originally established in our laboratory as a CD93 detection probe [17].
• This interaction was Ca(2+) independent and was not blocked by our anti-C1qRp mAb BIIG-4, but was blocked by the proadhesive mAb mNI-11 [18].

Physical interactions of CD93

• Calreticulin and C1q-R both bind to C1q and mannan-binding protein [14].
• It was independent of Candida-SP-A binding and phagocyte C1q receptor occupancy, but apparently demanded SP-A internalization by the mononuclear phagocytes, effecting down-regulation of proinflammatory cytokine synthesis at the transcriptional level [19].

Regulatory relationships of CD93

• Upon DL-1 signaling, Pax5-deficient pro-B cells down-regulate both surface CD93 expression and transcripts for B cell-specific genes and concomitantly up-regulate T lineage gene transcripts [20].
• In addition, both Go6976 and Rottlerin inhibited the up-regulation of CD93 expression induced by PMA and IL-8 or IFN-gamma production in the respective cell-lines [17].
• In addition, B cell CSPG blocked C1q receptor binding in a dose-dependent manner [21].

Other interactions of CD93

• C1qR/CRT is located on the surface of many cell types [11].
• Calreticulin, a candidate C1q receptor, was shown recently to be present on the surface of human neutrophils in association with glycosylphosphatidylinositol (GPI) anchored proteins, particularly CD59 [22].
• Recently, a novel 33-kDa C1q receptor (gC1qR) that interacts with the globular head region of C1q was identified on Raji cells, as well as PBLs, neutrophils, and eosinophils [23].
• The up-regulation of C1qR by inflammatory mediators and the ability of C1q itself to increase ICAM-1 expression suggest a potential role for these binding sites in vascular inflammation and immune injury [24].
• Antibodies to HK receptors on leukocytes including Mac-1, LFA-1, uPAR, and C1qR inhibited IL-1beta secretion induced by tKa 98%, 89%, 85%, and 62%, respectively [25].

Analytical, diagnostic and therapeutic context of CD93

• Use of glycosylation inhibitors, cleavage of the mature C1qRP with specific glycosidases, and in vitro translation of C1qRP cDNA demonstrated that both posttranslational glycosylation and the nature of the amino acid sequence of the protein contribute to the difference between its predicted m.w. and its migration on SDS-PAGE [15].
• Ligation of human monocytes with immobilized R3, a IgM mAb recognizing C1qRP, also triggers enhanced phagocytic capacity of these cells in the absence of ligand, verifying the direct involvement of this polypeptide in the regulation of phagocytosis [15].
• Using a DNA probe based on the coding region of the receptor, Northern blot and RT-PCR analysis of RNA isolated from different cell types showed C1qRP expression in cells of myeloid origin and in endothelial cells, but not in cells of lymphoid origin nor in the HeLa epithelial-like cell line or iliac artery smooth muscle cells [26].
• In addition, introduction of an antibody raised against the carboxy-terminal, cytoplasmic domain of C1qRp into microglia by electroporation markedly diminished the ability of C1q to enhance uptake of IgG-coated targets, whereas nonspecific IgG had no such effect [27].
• Sequence analysis revealed that CD93 is identical to a protein on human phagocytes termed C1q receptor (C1qRp) [12].

References