The role of complement component C3b and its receptors in sperm-oocyte interaction.

Abstract

Previous studies have shown that human sperm that have undergone the acrosome reaction express a unique tissue-specific variant of the complement component 3 (C3)-binding molecule membrane cofactor protein (MCP, CD46) and that damaged or dead sperm activate the alternative pathway of complement and bind C3 catabolites. In this study we provide evidence that MCP on sperm that have undergone the acrosome reaction specifically binds dimeric C3b and that human sperm acrosomal proteases released during the acrosome reaction directly cleave C3, facilitating its binding to MCP. Furthermore, human and hamster oocytes can activate the alternative pathway of complement and also bind human C3 fragments. Monoclonal antibodies specific for complement receptors type 1 (CD35) and type 3 (CD11b/CD18) bind to the human oocyte plasma membrane, indicating that specific complement-binding molecules may play a role in the attachment of C3 catabolites to oocytes. Subsaturating concentrations of dimeric C3b (0.01-1 FM) promoted penetration of hamster oocytes by human sperm, whereas saturating doses (>10 FM) inhibited this process. In addition, antibodies to both MCP and C3 signiicantly inhibited penetration of hamster oocytes by human sperm. These data provide evidence that regulated gamete-induced generation of C3 fragments and the binding of these fragments by selectively expressed receptors on sperm and oocytes may be an initial step in gamete interaction, leading to membrane fusion and fertilization.Mammalian fertilization entails a complex series of events including (i) attachment of sperm to the zona pellucida of the oocyte via receptors on the sperm plasma membrane; (ii) the sperm acrosome reaction (AR), exocytosis of the acrosomal contents from the acrosome, a specialized granule containing proteases and other degradative enzymes; (iii) penetration of sperm through the zona pellucida, which occurs concurrently with the AR; (iv) attachment of sperm to the oocyte plasma membrane (oolema) via receptors exposed on the sperm surface after the AR; and (v) sperm-oocyte fusion. Receptors and ligands mediating these events are only now beginning to be identified and characterized (1).Recently, we and others have shown that human sperm that have undergone the AR express membrane cofactor protein (MCP, CD46), a complement component 3 (C3)-binding and regulatory protein, on the inner acrosomal membrane (2-4). Sperm MCP has cofactor activity for factor I-mediated cleavage of C3, and one of its apparent functions is protection of sperm from the lytic consequences of complement resulting from interactions with antisperm antibodies (5). However, sperm MCP is a tissue-specific isoform characterized by differential glycosylation (5) and deletions resulting in a shorter transmembrane region and distinctive cytoplasmic tail (6); this suggests that sperm MCP may haveThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. ...

A Novel Chicken Membrane-Associated Complement Regulatory Protein: Molecular Cloning and Functional Characterization

“…The other SCR proteins Crry and MCP can serve as costimulators for proliferation of T cells and lead to secretion of IL-4 (36,37). In addition, most C regulatory proteins are expressed at high levels in the testicular germ cells in mammals (18,38), and their function may be related to fertilization (39,40). It is still unknown whether Cremp is expressed predominantly in chicken testicular germ cells and plays some roles in fertilization as speculated in mammals.…”

The mechanism of sperm–egg interaction and the involvement of IZUMO1 in fusion

“…Anderson et al provide evidence that regulated generation of complement C3 fragments by acrosomal enzymes and the binding of these fragments by CD46 on sperm and complement receptor 1 on eggs may be an initial step in gamete interaction, leading to membrane fusion. 25 In fact, several anti-human CD46 monoclonal antibodies effectively inhibit fertilization in in vitro fertilization. 26 Interestingly, mouse CD46 was found only in testis and the protein was found on the inner acrosomal membrane of sperm.…”

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