Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To discriminate self from non-self is an essential issue in the immune system. Autologous cells are protected against complement-mediated cell injury by the self-recognition mechanism using complement regulatory proteins composed of complement receptor type 1 (CR1, CD35), membrane cofactor protein (MCP, CD46), decay accelerating factor (DAF, CD55) and homologous restriction factor (protectin, CD59). Recently, the up-regulation of these molecules has been widely shown in inflammatory tissues and organs affected by autoimmune diseases, and in vitro assays have revealed that immune complexes or several cytokines, including interferongamma, tumor necrosis factor alpha, interleukin 1beta and transforming growth factor beta, can up-regulate these molecules. In contrast, it has been found that expression of these complement regulatory proteins is markedly decreased on autologous cells undergoing apoptosis. These findings suggest that complement regulatory proteins have dual roles at inflammatory sites: enhancement of cellular resistance to complement attack and acceleration of the clearance of cells injurious to the organism due to complement-mediated mechanisms. To assist the former function, a therapeutic approach using recombinant soluble complement regulatory proteins may provide a promising strategy for the treatment of autoimmune diseases.
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PMID:Complement regulatory proteins and autoimmunity. 1114 Apr 63

Previous studies have shown that DAF (or CD55), a cell surface inhibitor of autologous C3 activation, is present in tears and that > 90% of the C3 convertase regulatory activity in tear fluid resides in this protein (Lass JH et al., Invest Ophth Vis Sci 1990; 31:1136-48). This study investigated whether (i) the membrane cofactor protein (MCP or CD46), an additional factor that regulates C3 activation, and (ii) the membrane inhibitor of reactive lysis (MIRL or CD59), a cell surface regulator that acts to prevent formation of the membrane attack complex, are also present in tears, and if so, are functional. Two-site immunoradiometric assays showed that MCP is present in tears at low levels (42 + 8 ng/ml, n = 8) while CD59 is present at levels (222 + 78 ng/ml, n = 14) comparable to those of DAF (325 + 289 ng/ml, n = 12). The concentrations of CD59 (i) were increased two-fold or more in closed eye tears, and (ii) were decreased in reflex tears. Western blotting showed that CD59 protein in tears migrates with an apparent mol. wt similar to membrane CD59 protein. Phenyl-Sepharose adsorption and Triton X-114 partitioning of tear CD59 as well as of tear DAF however, showed that both proteins are devoid of GPI anchors. Assays using cobra venom factor-activated human serum and guinea pig erythrocytes showed that CD59 is functionally active in inhibiting autologous C5b-9-mediated lysis and, under constitutive conditions, accounts for > 85% of the C9 inhibitory activity in tear fluid.
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PMID:Tears contain the complement regulator CD59 as well as decay-accelerating factor (DAF). 1120 47

Pili of Neisseria gonorrhoeae mediate binding of the bacteria to human host cells. Membrane cofactor protein (MCP or CD46), a human cell-surface protein involved in regulation of complement activation, acts as a cellular pilus receptor. In this work, we examined which domains of CD46 mediate bacterial adherence. The CD46 expression was quantified and characterized in human epithelial cell lines. N. gonorrhoeae showed the highest adherence to ME180 cells, which have BC1 as the dominant phenotype. The BC isoforms of CD46 were expressed in all cell lines tested. The adherence was not enhanced by high expression of other isoforms, showing that the BC domain of CD46 is important in adherence of N. gonorrhoeae to human cells. To characterize the pilus-binding site within the CD46 molecule, a set of CD46-BC1 deletion constructs were transfected into COS-7 cells. Piliated N. gonorrhoeae attached well to CD46-BC1-expressing COS-7 cells. We show that the complement control protein repeat 3 (CCP-3) and the serine-threonine-proline (STP)-rich domain of CD46 are important for efficient adherence to host cells. Further, partial deletion of the cytoplasmic tail of CD46 results in low bacterial binding, indicating that the cytoplasmic tail takes part in the process of establishing a stable interaction between N. gonorrhoeae and host cells.
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PMID:Attachment of Neisseria gonorrhoeae to the cellular pilus receptor CD46: identification of domains important for bacterial adherence. 1126 Jan 36

The complement system plays an important role in host defense. However, if not properly regulated, activated complement can also cause significant damage to host tissues. To prevent complement-mediated autologous tissue damage, host cells express a number of membrane-bound complement regulatory proteins. These include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and CD59. Recent studies of membrane complement regulatory proteins from various animal species have revealed similarities as well as significant differences from the corresponding human proteins. In this review, we summarize recent advances in this area and contrast the structure, function and tissue distribution of membrane complement regulatory proteins in human and nonprimate mammalian species. We also discuss how the characterization of the animal proteins has provided important clues and might continue to show relevance to the pathogenesis and therapeutics of a number of human diseases.
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PMID:Membrane complement regulatory proteins: insight from animal studies and relevance to human diseases. 1136 29

Human membrane cofactor protein (MCP; CD46) is a widely distributed complement regulator. In the mouse, expression of MCP is largely restricted to the testis while a related, widely expressed protein (Crry) appears to perform MCP's (CD46) regulatory activity. We have developed two mouse strains transgenic for human MCP (CD46) utilizing an approximately 400 kb YAC clone carrying the complete gene. A third mouse strain was generated using an overlapping YAC clone isolated from a second library. The expression of human MCP (CD46) in these mouse strains was characterized by immunohistochemistry, FACS, Western blotting and RT-PCR. No differences were detected in the isoform pattern or distribution among the three strains, although the expression level varied according to how many copies of the gene were integrated. The expression profile closely mimicked that observed in humans, including the same pattern of isoform expression as the donor. In addition, tissue-specific isoform expression in the kidney, salivary gland and brain paralleled that observed in man. The transgenic mice expressed low levels of MCP (CD46) on their E, in contrast to humans but in line with most other primates. These mice should be a useful tool to analyse tissue-specific expression, to establish animal models of infections and to characterize the role of MCP (CD46) in reproduction.
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PMID:Membrane cofactor protein (MCP; CD46) expression in transgenic mice. 1142 93

CD59 and membrane cofactor protein (MCP, CD46) are widely expressed cell surface glycoproteins that protect host cells from the effect of homologous complement attack. cDNAs encoding human CD59 and MCP cloned from Chinese human embryo were separately transfected into NIH/3T3 cells resulting in the expression of human CD59 and MCP protein on the cell surface. The functional properties of expressed proteins were studied. When the transfected cells were exposed to human serum as a source of complement and naturally occurring anti-mouse antibody, they were resistant to human complement-mediated cell killing. However, the cells remained sensitive to rabbit and guinea pig complement. Human CD59 and MCP can only protect NIH/3T3 cells from human complement-mediated lysis. These results demonstrated that complement inhibitory activity of these proteins is species-selective. The cDNAs of CD59 and MCP were also separately transfected into the endothelial cells (ECs) of the pigs transgenic for the human DAF gene to investigate a putative synergistic action. The ECs expressing both DAF and MCP proteins or both DAF and CD59 proteins exhibited more protection against cytolysis by human serum compared to the cells with only DAF expressed alone.
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PMID:Protection of xenogeneic cells from human complement-mediated lysis by the expression of human DAF, CD59 and MCP. 1172 Aug 16

Previously we have shown that two members of the newly named SIBLING (small integrin-binding ligand, N-linked glycoproteins) family of proteins, bone sialoprotein, and osteopontin, bound first to a cell surface receptor and then to complement Factor H thereby blocking the lytic activity of the alternative pathway of complement. Another member of this family, dentin matrix protein 1, is shown in this paper to be very similar to osteopontin in that it can bind strongly to Factor H (K(a) approximately 1 nm) and block the lytic activity through either the vitronectin receptor (alpha(V)beta(3) integrin) or CD44. Binding of Factor H to SIBLING localized to the cells surface was demonstrated by fluorescence-activated cell sorting. Extensive overlapping fragment analyses suggests that both dentin matrix protein 1 and osteopontin interact with cell surface CD44 through their amino termini. Similar fragments of bone sialoprotein, like the intact protein, did not functionally interact with CD44. All three proteins are shown to act in conjunction with Factor I, a serum protease that, when complexed to appropriate cofactors, stops the lytic pathway by digesting the bound C3b in a series of proteolytic steps. These results show that at least three members of this family confer membrane cofactor protein-like activity (MCP or CD46) upon cells expressing RGD-binding integrins or CD44. The required order of the assembly of the complex suggests that this cofactor activity is limited to short diffusional distances.
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PMID:Three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) enhance factor H's cofactor activity enabling MCP-like cellular evasion of complement-mediated attack. 1182 98

All human blood cells express decay-accelerating factor (DAF, CD55), CD59, and, with the exception of erythrocytes, membrane cofactor protein (MCP, CD46) to protect themselves from damage by the constant low-level activation of complement in serum. In rats and mice MCP is expressed only in testis, whereas DAF and CD59 are broadly distributed. Rats and mice also express a unique complement regulator, Crry. Previously we have shown that DAF was absent from at least 75% of rat T cells. To further investigate this surprising finding, we assessed the expression levels of DAF, CD59 and Crry on all blood cell types in the rat. We found that Crry was abundantly expressed on all blood cells. CD59 was expressed abundantly on erythrocytes and granulocytes but was absent from all T cellsand platelets and a minority of B cells and NK cells. Double staining and depletion studies showed that T cells in all rat strains tested were DAF-CD59-. Neutralization of Crry using a blocking monoclonal antibody rendered T cells susceptible to lysis by homologous complement, indicating that Crry was solely responsible for protecting DAF-CD59- T cells from complement damage in the rat.
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PMID:Rat T cells express neither CD55 nor CD59 and are dependent on Crry for protection from homologous complement. 1182 67

Xenotransplantation is being pursued vigorously to solve the shortage of allogeneic donor organs. Experimental studies of the major xenoantigen (Gal) and of complement regulation enable model xenografts to survive hyperacute rejection. When the Gal antigen is removed or reduced and complement activation is controlled, the major barriers to xenograft survival include unregulated coagulation within the graft and cellular reactions involving macrophages, neutrophils, natural killer (NK) cells, and T lymphocytes. Unlike allografts, where specific immune responses are the sole barrier to graft survival, molecular differences between xenograft and recipient that affect normal receptor-ligand interactions (largely active at the cell surface and which may not be immunogenic), are also involved in xenograft failure. Transgenic strategies provide the best options to control antigen expression, complement activation, and coagulation. Although the Gal antigen can be eliminated by gene knockout in mice, that outcome has only become a possibility in pigs due to the recent cloning of pigs after nuclear transfer. Instead, the use of transgenic glycosyl transferase enzymes and glycosidases, which generate alternative terminal carbohydrates on glycolipids and glycoproteins, has reduced antigen in experimental models. As a result, novel strategies are being tested to seek the most effective solution. Transgenic pigs expressing human complement-regulating proteins (DAF/CD55, MCP/CD46, or CD59) have revealed that disordered regulation of the coagulation system requires attention. There will undoubtedly be other molecular incompatibilities that need addressing. Xenotransplantation, however, offers hope as a therapeutic solution and provides much information about homeostatic mechanisms.
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PMID:Genetic engineering for xenotransplantation. 1192 25

C4b and C3b deposited on host cells undergo limited proteolytic cleavage by regulatory proteins. Membrane cofactor protein (MCP; CD46), factor H, and C4b binding protein mediate this reaction, known as cofactor activity, that also requires the plasma serine protease factor I. To explore the roles of the fluid phase regulators vs those expressed on host cells, a model system was used examining complement fragments deposited on cells transfected with human MCP as assessed by FACS and Western blotting. Following incubation with Ab and complement on MCP(+) cells, C4b was progressively cleaved over the first hour to C4d and C4c. There was no detectable cleavage of C4b on MCP(-) cells, indicating that MCP (and not C4BP in the serum) primarily mediates this cofactor activity. C3b deposition was not blocked on MCP(+) cells because classical pathway activation occurred before substantial C4b cleavage. Cleavage, though, of deposited C3b was rapid (<5 min) and iC3b was the dominant fragment on MCP(-) and MCP(+) cells. Studies using a function-blocking mAb further established factor H as the responsible cofactor. If the level of Ab sensitization was reduced 8-fold or if Mg(2+)-EGTA was used to block the classical pathway, MCP efficiently inhibited C3b deposition mediated by the alternative pathway. Thus, for the classical pathway, MCP is the cofactor for C4b cleavage and factor H for C3b cleavage. However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation.
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PMID:Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. 1205 45


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