Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism.

Abstract

SummaryThe cleavage of C3 is a critical step for complement (C) activation in the classical and alternative pathways. This reaction is controUed by the regulators of C activation protein family. Membrane cofactor protein (MCP) is a cofactor for the factor I-mediated inactivation of C3b and C4b. As a widely distributed membrane protein, MCP may protect host cells from inadvertent C activation. Human MCP has recently been shown to protect transfected rodent cells from human C-mediated lysis. In this report the relationship of MCP expression to C3b deposition and cytoprotection was examined using NIH/3T3 cells transfected with human MCP and exposed to human serum as a source of C and naturally occurring anti-mouse antibody. MCP inhibited C3b deposition in a dose-dependent fashion and inhibited lysis of the mouse cells expressing it. MCP did not inhibit lysis on bystander cells. These results demonstrate the protective role of MCP, at the cellular level, by an intrinsic mechanism.T he human C system is an independent immune system that can separate self from nonself and function as a potent effector system (1). C components are spontaneously and continuously deposited on self tissue in small amounts (2), and in larger quantities during inflammatory reactions. Membrane cofactor protein (MCP; 1 CD46) and decay-accderating factor (DAF; CD55) are membrane glycoproteins that protect host cells from damage by the C system (reviewed in references 3 and 4). MCP is a cofactor for the factor I-mediated cleavage of C3b and C4b, while DAF accelerates decay dissociation of the C3 and C5 convertases. Both proteins are widely distributed on hematopoietic, endothelial, and epithdial cells. They are also highly expressed on certain malignant cell lines (3-7) and reproductive tissues (8).DAF is a glycolipid-anchored protein and functions intrinsically; that is, it protects only the cell on which it is expressed (9). The same mechanism has been postulated for MCP (3,10,11). Although experiments to date are consistent with this interpretation (11-15), the question has not been directly tested.Oglesby et al. (14), Atkinson et al. (15), and Lublin and Abbreviations used in this paper: DAF, decay-accderating factor; MCP, membrane cofactor protein; NHS, normal human serum.Coyne (13) have used nonhuman cell lines transfected with the human MCP or DAF gene to demonstrate the capacity of these proteins to protect cells from C-mediated damage. Seya et al. (12) have also shown that human T cell lines expressing MCP but no other C regulatory protein became susceptible to lysis by the alternative pathway if the activity of MCP was blocked by a mAb. To further assess the mechanism of the inhibitory effect of MCP on C activation, mouse fibroblasts were transfected with human MCP and then exposed to human serum. Only those cells on which MCP was expressed were protected from lysis by human C. This intrinsic mechanism of cytoprotection by MCP and the quantitative aspects of its activity could be of interest to tumor, transplant, and reproductive imm...

Membrane Cofactor Protein (MCP; CD46): Isoform-Specific Tyrosine Phosphorylation

“…But MCP lacks receptor function. It inefficiently binds C3b-or C4b-bearing fluid-phase or cell-bound immune complexes (1,45). Thus, MCP's role is to transiently interact with either of these ligands bound to its "home" cell.…”

“…2, 3, and 7). MCP binds these two ligands efficiently if they are attached to the same cell on which MCP itself is expressed (45). But MCP lacks receptor function.…”

Complement regulatory proteins are incorporated into lentiviral vectors and protect particles against complement inactivation

“…One group of proteins, including CD55/ decay accelerating factor (DAF) and CD46/membrane cofactor protein (MCP), inhibits the classical and alternative pathway C3/C5 convertase enzymes. 24,25 Another set of proteins including CD59 regulates MAC assembly. 26 CRPs have been used to prevent rejection of xenotransplanted tissues and have also been shown to protect viruses and viral vectors from complement inactivation.…”

Cooperation Between Decay-Accelerating Factor and Membrane Cofactor Protein in Protecting Cells from Autologous Complement Attack

“…Previous studies of cell-associated MCP function have relied principally on cytotoxicity assays of transfectants in whole serum (2,19,20). As an initial approach for directly assaying MCP's function on the cell surface, biotinylated C3b was deposited during the last amplification step (see Materials and Methods) on E rab C3b (18) showed that 2.1 Ϯ 0.2% of the added protein uniformly incorporated, and preliminary control experiments showed that the proteins incorporated with equal efficiencies (DAF, 2.1 Ϯ 0.3%; MCP, 1.9 Ϯ 0.2%).…”