Disease relevance of CD46

• The human CD46 molecule is a receptor for measles virus (Edmonston strain) [1].
• CD46 is a cellular receptor for human herpesvirus 6 [2].
• Rather, they support a model in which pilus interaction with CD46 promotes signaling cascades important for Neisseria infectivity [3].
• Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome [4].
• Expression of complement inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma [5].

Psychiatry related information on CD46

• The molecular complex involving CD46 may confer high MV permissiveness leading to immune modulation in Mphi [6].
• The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p less than 0.05), with specific worsening of PANSS-positive symptoms (p less than 0.025) and PANSS activation (p less than 0.001) [7].
• Normal controls (NC) (n = 15), patients with panic disorder (PD) (n = 13) and patients with major depression (MD) (n = 17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo [8].
• However, correlations were found between MCP and neuroticism and extroversion scores from a personality inventory and physical variables [9].
• However, the observed anxiogenic properties of MCPP suggest that additional studies of the role of serotonin systems in the pathophysiology of human anxiety disorders are indicated [10].

High impact information on CD46

• Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster [11].
• Downregulation of surface CD46 was documented during the course of HHV-6 infection [2].
• Both acute infection and cell fusion mediated by HHV-6 were specifically inhibited by a monoclonal antibody to CD46; fusion was also blocked by soluble CD46 [2].
• We proved this hypothesis by demonstrating that hamster cell lines that expressed human CD46 could subsequently bind virus [1].
• A study of lymphocyte markers suggested that the complement regulator known either as membrane cofactor protein or CD46 was the measles virus receptor [1].

Chemical compound and disease context of CD46

• CD46 is phosphorylated at tyrosine 354 upon infection of epithelial cells by Neisseria gonorrhoeae [3].
• CD46 from nuclear and membrane stores was found to cluster into blebs and shed into microparticles together with NA, phosphatidylserine, C1q, and factor H. Classical and alternative pathways of complement were involved in the recognition of H2O2-treated necrotic cells [12].
• Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function [13].
• In this study we have characterised the C3/C5 convertase regulators DAF and MCP on the human colonic adenocarcinoma cell line HT29 [14].
• Human herpesvirus 6 (HHV-6) glycoproteins H and L (gH and gL, respectively) and the 80-kDa form of glycoprotein Q (gQ-80K) form a heterotrimeric complex that is found on the viral envelope and that is a viral ligand for human CD46 [15].

Biological context of CD46

• Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype [16].
• Here, we report that infection of human epithelial cells by piliated Neisseria gonorrhoeae (GC) leads to rapid tyrosine phosphorylation of CD46 [3].
• CD46 mutants with truncated cytoplasmic tails fail to support bacterial adhesion (Källström et al., 2001), suggesting that this region of the molecule also plays an important role in infection [3].
• We examined the activities of recombinant variants of CD46, including different isoforms as well as engineered truncations and molecular chimeras with decay-accelerating factor, a related protein in the family of regulators of complement activation (RCA) [13].
• Ligand binding to CD46 affects (i) protection of autologous cells from complement attack by breakdown of complement components, (ii) intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv) down-regulation of cell surface CD46 [17].

Anatomical context of CD46

• Furthermore, infected CD46+ cells produced syncytia and viral proteins [1].
• These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype [16].
• We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46 [12].
• Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites [12].
• However, cross-linking of CD46 at the cell surface, by either multivalent antibody or by measles virus, induces pseudopodia that engulf the ligand in a process similar to macropinocytosis, and leads to the degradation of cell surface CD46 [17].

Associations of CD46 with chemical compounds

• The pilus binds CD46, a complement-regulatory glycoprotein present on nucleated human cells (Källström et al., 1997) [3].
• Studies with wild-type and mutant tail fusion constructs demonstrate that Src kinase phosphorylates tyrosine 354 in the Cyt2 isoform of the CD46 cytoplasmic tail [3].
• These data, together with cross-linking experiments showing the existence in living cells of CD46/integrin complexes, suggest that CD46 associates directly with beta1 integrins and indirectly with tetraspans [18].
• Multiple molecular weight isoforms of membrane bound CD46 are produced by alternative splicing of the CD46 mRNA in an area coding for the serine/threonine/proline-rich region or for the cytoplasmic tail [19].
• Exposure of the cells to hydrogen peroxide (H2O2) or their detachment from the pericellular matrix increased the shedding of soluble CD46 [19].

Physical interactions of CD46

• The surface M protein of GAS binds CD46 and mediates GAS adherence to keratinocytes [20].

Regulatory relationships of CD46

• CD46 also enhanced IL-2 or IFN-gamma secretion by CD4+ blasts [21].
• Since CD46 was consistently expressed in colorectal carcinomas the low expression or even lack of CD59 in a subset of tumours might not lead to critical complement-mediated attack of CD59-negative tumour cells [22].
• IFN-gamma downregulated expression of CD46 on one cell line (p < 0.01) [23].
• Indeed, we show in this study that CD46/CD3 costimulation induces a synergistic activation of extracellular signal-related kinase mitogen-activated protein kinase [24].
• Cross-linking CD46 alone induced weak tyrosine phosphorylation of CD3zeta and ZAP-70 [21].

Other interactions of CD46

• Thus, CD46, CD55, and CD59 expression on pretreatment tumor cells, or their susceptibility to in vitro complement-mediated killing, does not predict clinical outcome after rituximab treatment [5].
• The effect of CD46 on IL-10 secretion did not require additional costimuli like anti-CD28 antibodies or phorbol esters [21].
• However, CD46 cross-linking by itself did not induce cell proliferation or lymphokine secretion, and pretreatment of CD4+ T lymphocytes with anti-CD46 antibodies did not significantly alter TCR/CD3 activation [21].
• A functional analysis of recombinant soluble CD46 in vivo and a comparison with recombinant soluble forms of CD55 and CD35 in vitro [25].
• Expression of CD59, a complement regulator protein and a second ligand of the CD2 molecule, and CD46 in normal and neoplastic colorectal epithelium [22].

Analytical, diagnostic and therapeutic context of CD46

• Ad3 colocalized with cell surface CD46 in both rodent and human cells at the light and electron microscopy levels [26].
• We have examined the relative mRNA expression of the complement (C) regulatory proteins CD59, CD55 and CD46 in RNA isolated from 50 primary breast cancer specimens using a semiquantitative RT-PCR approach [27].
• A recombinant soluble chimeric complement inhibitor composed of human CD46 and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation [28].
• We observed that tumor cells liberated intact 60-65 kDa forms of CD46 into the cell culture medium on the surface of vesicles with a diameter of 200 nm [19].
• Transgenic pigs expressed high levels of CD46 in all tissues, especially vascular endothelium, with stable expression through three generations that was readily monitored by flow cytometry of transgenic peripheral blood mononuclear cells (PBMC) [29].

References