Complement regulator CD46: genetic variants and disease associations

Abstract

Membrane cofactor protein (MCP; CD46) is an ubiquitously expressed complement regulatory protein that protects host cells from injury by complement. This type-I membrane glycoprotein serves as a cofactor for the serine protease factor I to mediate inactivation of C3b and C4b deposited on host cells. More than 60 disease-associated mutations in MCP have now been identified. The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified. This review summarizes our current knowledge of disease-associated mutations in this complement inhibitor.

Fig 1

Complement function. The two primary functions of the complement system are to modify pathogens and self-debris with clusters of complement fragments (opsonization). This, in turn, facilitates interaction with complement receptors and, in some bacteria and viruses, induces lysis. The second function is to promote the inflammatory response. Complement fragments C3a and C5a generated during activation of the cascades stimulate many cell types. In the case of mast cells, release of immunomodulatory granules also attracts phagocytic cells into the area of inflammation (chemotaxis)

Fig. 2

The complement cascades. The three pathways of complement activation are shown. Although each is triggered independently, they merge at the step of C3 activation. The CP is initiated by the binding of antibody to antigen and the lectin pathway by the binding of lectin to a sugar. The alternative pathway turns over continuously and possesses a feedback loop (see Fig. 3). Activation of the complement system leads to inflammation, opsonization, and membrane perturbation. Abbreviations: MASP MBL-associated serine protease, MBL mannose-binding lectin, FB factor B, FD factor D, P properdin

Fig. 3

Feedback loop of the alternative pathway. Following the attachment of C3b to its target, a feedback loop can be engaged via interactions with the two proteases, factor B (FB) and factor D (FD), to form the AP C3 convertase. The binding of properdin (P) stabilizes the complex (i.e., its half-life is increased from 30–40 s to 3–4 min). Within a few minutes, more than one million C3bs can be generated and bound to a single bacterium

Fig. 4

Cofactor activity of CD46 illustrated for the alternative pathway. CD46 binds to C3b that becomes attached to host cells. This then allows the serine protease factor I to cleave C3b into iC3b that cannot participate in the feedback loop. CD46 is nearly ubiquitously expressed on human cells

Fig. 5

Disease-associated CD46 mutations. A schematic depicting CD46 protein, genomic organization, and disease-associated amino acid mutations. CD46 has a 34-amino-acid signal peptide (SP). The mature protein consists of four complement control protein (CCP) repeats that house the sites for regulatory activity. This is followed by an alternatively spliced region for O-glycosylation (segments A, B, C), a segment of undefined function (U), a transmembrane domain (TM), and one of two alternatively spliced cytoplasmic tails (CYT-1 or CYT-2). The gene consists of 14 exons and 13 introns for a minimum length of 43 kb. A majority of mutations for aHUS and for other disorders (such as systemic sclerosis, systemic lupus erythematosus, and pregnancy-related disorders) occur in the four CCPs. Black, aHUS mutations; red, aHUS and other diseases; green, non-aHUS disease